N-substituted nonaryl-heterocyclo amidyl NMDA/NR2B Antagonists

ABSTRACT

Compounds represented by Formula (I): 
                         
or pharmaceutically acceptable salts thereof, are effective as NMDA NR2B antagonists useful for relieving pain.

RELATED APPLICATION DATA

This application claims the benefit of U.S. provisional application60/281,166, which was filed Apr. 3, 2001.

BACKGROUND OF THE INVENTION Field of the Invention

This invention relates to N-substituted nonarylheterocyclo amidylcompounds. In particular, this invention relates to N-substitutednonarylheterocyclo amidyl compounds that are effective as NMDA NR2Bantagonists useful for relieving pain.

Ions such as glutamate play a key role in processes related to chronicpain and pain-associated neurotoxicity—primarily by acting throughN-methyl-D-aspartate (“NMDA”) receptors. Thus, inhibition of suchaction—by employing ion channel antagonists, particularly NMDAantagonists—can be beneficial in the treatment and control of pain.

Known NMDA antagonists include ketamine, dextromophan, and3-(2-carboxypiperazin4-yl)-propyl-1-phosphonic acid (“CPP”). Althoughthese compounds have been reported (J. D. Kristensen, et al., Pain,51:249–253 (1992); P. K. Eide, et al., Pain, 61:221–228 (1995); D. J.Knox, et al., Anaesth. Intensive Care 23:620–622 (1995); and M. B. Max,et al., Clin. Neuropharmacol. 18:360–368 (1995)) to produce symptomaticrelief in a number of neuropathies including postherpetic neuralgia,central pain from spinal cord injury, and phantom limb pain, widespreaduse of these compounds is precluded by their undesirable side effects.Such side effects at analgesic doses include psychotomimetic effectssuch as dizziness, headache, hallucinations, dysphoria, and disturbancesof cognitive and motor function. Additionally, more severehallucinations, sedation, and ataxia are produced at doses onlymarginally higher than analgesic doses. Thus, it would be desirable toprovide novel NMDA antagonists that are absent of undesirable sideeffects or that produce fewer and/or milder side effects.

NMDA receptors are heteromeric assemblies of subunits, of which twomajor subunit families designated NR1 and NR2 have been cloned. Withoutbeing bound by theory, it is generally believed that the variousfunctional NMDA receptors in the mammalian central nervous system(“CNS”) are only formed by combinations of NR1 and NR2 subunits, whichrespectively express glycine and glutamate recognition sites. The NR2subunit family is in turn divided into four individual subunit types:NR2A, NR2B, NR2C, and NR2D. T. Ishii, et al., J. Biol. Chem.,268:2836–2843 (1993), and D. J. Laurie et al., Mol. Brain Res., 51:23–32(1997) describe how the various resulting combinations produce a varietyof NMDA receptors differing in physiological and pharmacologicalproperties such as ion gating properties, magnesium sensitivity,pharmacological profile, as well as in anatomical distribution.

For example, while NR1 is found throughout the brain, NR2 subunits aredifferentially distributed. In particular, it is believed that thedistribution map for NR2B lowers the probability of side effects whileproducing pain relief. For example, S. Boyce, et al., Neuropharmacology,38:611–623(1999) describes the effect of selective NMDA NR2B antagonistson pain with reduced side effects. Thus, it would be desirable toprovide novel NMDA antagonists that target the NR2B receptor. Suchantagonists would be useful in the treatment of pain, migraine,depression, anxiety, schizophrenia, Parkinson's disease, stroke,glaucoma, or tinitis—maladies that are amenable to amelioration throughinhibition of NMDA NR2B receptors.

U.S. Pat. No. 6,020,347 and International Patent Publication WO99/25685describes 4-substituted-4-piperidine carboxamide derivatives that areantagonists of VLA-4 (“Very Late Antigen-4”). International PatentPublication WO 01/00207 describes substituted pyrimidine compounds thatare inhibitors of tyrosine kinases. International Patent Publication WO00/61551 describes oxopyrimidinealkanoate compounds that areintegrin-receptor ligands. International Patent Publication EP 604800describes carboxyalkyl-phenyl aminocarbonyl-phenyl-piperidine compoundsthat are blood platelet aggregation inhibitors. International PatentPublication EP 611660 describes benzimidazoles, xanthines, and analogsas tissue aggregation inhibitors. International Patent Publication EP771799 and U.S. Pat. No. 5,861,396 describe purin-6-one derivatives forthe treatment of cardiovascular and urogenital diseases. InternationalPatent Publication WO94/21615 describes benzimidazole-piperidinecompounds utilized as dopamine D4 antagonists. German Patent No.DE4241632 describes substituted phenyl or cyclohexyl-carboxylic acidderivatives that inhibit cell aggregation.

International Patent Publication WO 00/25786 describes heterocyclicpotassium channel inhibitors. International Patent Publication WO00/08015 describes non-peptidic amino derivatives that are folliclestimulating hormone agonists for the treatment of infertility.International Patent Publication WO 98/46589 describes indazole amidecompounds as serotoninergic agents. International Patent Publication WO98/05336 describes compounds that are inhibitors of cysteine protease.International Patent Publication WO 98/04913 describes pharmacophoremodels of integrin VLA-4 inhibitors. International Patent Publication WO97/45119 describes the use of substance P antagonists for treatingsocial phobia. International Patent Publication WO 97/28141 describesaromatic piperazines derived from substituted cycloazanes. InternationalPatent Publication WO 97/28139 describes naphthylpiperazines derivedfrom substituted cycloazanes. International Patent Publication WO96/34856 describes 2-ureido-benzamide derivatives. International PatentPublication WO 96/10035 describes inhibitors of farnesyl-proteintransferase. International Patent Publication WO 94/20062 describesbalanoids. International Patent Publication WO 94/14776 describesbicyclic fibrinogen antagonists. International Patent Publication EP532456 describes 1-acylpiperidine derivatives used as substance-Pantagonists. International Patent Publication WO/19709 describesimidazolylbenzoyl substituted heterocycles. Japanese Patent PublicationJP 10120644 describes 2-ureido-benzamide derivatives for treatingACAT-related diseases. International Patent Publication WO 00/11002describes 9-dialkylamino purinone derivatives. International PatentPublication WO 98/31669 describes arylpiperazine antidepressants derivedfrom piperidine. International Patent Publication WO 98/31677 describesaromatic amines derived from cyclic amines. R. D. Clark et al., J. Med.Chem., 26:855–861(1983) describes antihypertensive 9-subtituted1-oxa-4,9-diazaspiro[5.5]undecan-3-ones.

Phenol compounds described as NMDA antagonists are described in U.S.Pat. Nos. 5,306,723 and 5,436,255, and in International PatentPublications WO91/17156, WO92/19502, WO93/02052, WO96/37226, and EP441506. Benzyl piperidine substituted with phenols or imidazoles aredescribed in Z. L. Zhou, et al., J. Medicinal Chemistry,42:2993–3000(1999); T. F. Gregory, et al., Poster #94, 218^(th) NationalMeeting American Chemical Society, New Orleans, La., Aug. 22–26, 1999.Other NMDA NR2B selective compounds are described in European PatentPublication EP 787493 and J. N. C. Kew et al., British J. Pharmacol.,123:463(1998). However, there continues to be a need for novel NMDAantagonists that target the NR2B receptor.

SUMMARY OF THE INVENTION

The present invention relates to N-substituted nonarylheterocycliccompounds represented by Formula (I):

or pharmaceutically acceptable salts thereof. The present invention alsoforms pharmaceutical compositions utilizing the compounds. Further, thisinvention includes novel methods to treat pain by utilizing thecompounds.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of this invention are represented by Formula (I):

or pharmaceutically acceptable salts thereof, wherein

NonAr is a nonaromatic 5–7 membered ring containing a) 1 nitrogen ringatom, b) 2 nitrogen ring atoms, c) 1 nitrogen and 1 oxygen ring atom, ord) 1 nitrogen and 1 sulfur ring atom, wherein the remaining ring atomsare carbon;

A is a phenyl optionally substituted with 1–5 substituents, eachsubstituent independently is C₁₋₄alkyl, C₃₋₇cycloalkyl, —CF₃, halogen,—OH, —CN, imidazolyl, —C₀₋₄alkyl-N(C₀₋₅alkyl)(C₀₋₅alkyl), —O—C₁₋₄alkyl,—C(O)—C₀₋₄alkyl, —C(O)—O—C₀₋₄alkyl, —O—C(O)—C₀₋₄alkyl,—O—C(O)—C₀₋₄alkylphenyl, —C₀₋₄alkyl-N(C₀₋₅alkyl)—C(O)—C₀₋₄alkyl,—C₀₋₄alkyl-N(C₀₋₅alkyl)—C(O)—O—C₀₋₄alkyl,—C₀₋₄alkyl-N(C₀₋₅alkyl)—C(O)—O—C₁₋₄alkyl, or —NHSO₂—C₁₋₄alkyl,—O—C₁₋₄alkylphenyl, or hydroxyiminoethyl; any alkyl optionallysubstituted with 1–6 —OH or halogen; or

A is pyrrolyl, imidazolyl, pyrazolyl, triazolyl, thiophenyl, thiazolyl,thiadiazolyl, oxazolyl, or isoxazolyl, each optionally substituted with1–3 substituents, each substituent independently is —C₁₋₄alkyl,—C₃₋₇cycloalkyl, —CF₃, halogen, —OH, —CN, —C₁₋₄alkoxyl, phenyl,—C₀₋₄alkyl-N(C₀₋₅alkyl)(C₀₋₅alkyl), —C₁₋₄hydroxyalkyl; or

A is pyridyl, pyradazinyl, pyrimidinyl, or pyrazinyl, each optionallysubstituted with 1–5 substituents; each substituent independently is—C₁₋₄alkyl, —C₃₋₇cycloalkyl, —CF₃, halogen, —OH, —CN, phenyl,pyrrolidinyl, azepanyl, —C₁₋₄hydroxyalkyl, —C₁₋₄alkoxy,(CH₃)₂N—(CH₂)₂—NH—, —SO₂—C₁₋₄alkyl, —C₀₋₄alkyl-N(C₀₋₅alkyl)(C₀₋₅alkyl),—C₀₋₄alkyl-N(C₃₋₆cycloalkyl)(C₀₋₅alkyl),—C₀₋₄alkyl-N(C₀₋₅alkyl)(C₁₋₄alkyloxyC₁₋₄alkyl),—N(C₀₋₅alkyl)-C₀₋₄alkyl-phenyl(C1–4alkoxyl)₀₋₃,—N(C₀₋₅alkyl)—C₀₋₄alkylthiaphenyl, dimethoxyphenyl-CH₂—NH—; any phenyloptionally substituted with 1–5 —OH, halogen, or C₁₋₄alkyl; any alkyloptionally substituted with 1–5 —OH or halogen; or the substituent takenwith a neighboring bond is ═O; or

A is pyrrolophenyl, imidazolophenyl, pyrazolophenyl, triazolophenyl,pyridinoimidazolyl, naphthyridinyl, tetrahydrocyclopentopyrazolyl,quinolinyl, pyrimidinopyrazololyl, benzothiazolyl, benzoimidazolyl,benzoxazolonyl, oxodihydrobenzoxazolyl, indolinonyl,oxadihydroquinolinyl, oxatetrahydroquinolinyl, or purinyl, eachoptionally substituted with 1–5 substituents, each substituentindependently is —C₁₋₄alkyl, —C₃₋₇cycloalkyl, —CF₃, halogen, —OH, or—CN;

B is aryl(CH₂)₀₋₃—O—(CH₂)₀₋₂—C(O)—, heteroaryl(CH₂)₁₋₃—O—(CH₂)₀₋₂—(O)—,indanyl(CH₂)₀₋₃—O—(CH₂)₀₋₂—C(O)—, aryl(CH₂)₁₋₃—C(O)—(CH₂)₀₋₂—,aryl-cyclopropyl-C(O)—(CH₂)₀₋₂—, heteroaryl(CH₂)₁₋₃—C(O)—,aryl(CH₂)₁₋₃—, heteroaryl(CH₂)₁₋₃—, aryl(CH₂)₁₋₃—NH—C(O)—,aryl(CH₂)₁₋₃—NH—C(NCN)—, aryl(CH₂)₁₋₃—SO₂—,aryl(CH₂)₀₋₃—S—(CH₂)₀₋₂—C(O)—, or heteroaryl(CH₂)₁₋₃—SO₂— wherein any ofthe aryl or heteroaryl is optionally substituted by 1–5 substituents,each substituent independently is C₁₋₄alkyl, C₃₋₆cycloalkyl, C₁₋₄alkoxy,trifluoromethyl, phenyl, —O—C₁₋₄alkylphenyl, —S(O)—C₁₋₄alkyl, bromo,fluoro, chloro, or 2 substituents together form methylene dioxy; any(CH₂) optionally is substituted with C₁₋₂alkyl; or

B is

wherein the phenyl is optionally substituted by 1–3 substituents, eachsubstituent independently is C₁₋₄alkyl, C₃₋₆cycloalkyl, C₁₋₄alkoxy,trifluoromethyl, bromo, fluoro, or chloro; and

X is H, OH, F, C₁₋₄alkyl, C₁₋₄alkoxy, —N(C₀₋₅alkyl)(C₀₋₅alkyl), phenyl,or ═O.

In one aspect, the compounds of this invention are represented byFormula (I) or pharmaceutically acceptable salts thereof, wherein

NonAr is a nonaromatic 6 membered ring containing 1 nitrogen ring atom,wherein the remaining ring atoms are carbon;

A is a phenyl optionally substituted with 1–5 substituents, eachsubstituent independently is C₁₋₄alkyl, C₃₋₇cycloalkyl, —CF₃, halogen,—OH, —CN, imidazolyl, —C₀₋₄alkyl-N(C₀₋₅alkyl)(C₀₋₅alkyl), —O—C₁₋₄alkyl,—C(O)—C₀₋₄alkyl, —C(O)—O—C₀₋₄alkyl, —O—C(O)—C₀₋₄alkyl,—O—C(O)—C₀₋₄alkylphenyl, —C₀₋₄alkyl-N(C₀₋₅alkyl)-C(O)—C₀₋₄alkyl,—CO₄alkyl-N(C₀₋₅alkyl)-C(O)—O—C₀₋₄alkyl,—C₀₋₄alkyl-N(C₀₋₅alkyl)-C(O)—O—C₁₋₄alkyl, or —NHSO₂-C₁₋₄alkyl,—O—C₁₋₄alkylphenyl, or hydroxyiminoethyl; any alkyl optionallysubstituted with 1–6 —OH or halogen; or

A is pyrrolyl, imidazolyl, pyrazolyl, triazolyl, thiophenyl, thiazolyl,thiadiazolyl, oxazolyl, or isoxazolyl, each optionally substituted with1–3 substituents, each substituent independently is —C₁₋₄alkyl,—C₃₋₇cycloalkyl, —CF₃, halogen, —OH, —CN, —C₁₋₄alkoxyl, phenyl,—C₀₋₄alkyl-N(C₀₋₅alkyl)(C₀₋₅alkyl), —C₁₋₄hydroxyalkyl; or

A is pyridyl, pyradazinyl, pyrimidinyl, or pyrazinyl, each optionallysubstituted with 1–5 substituents; each substituent independently is—C₁₋₄alkyl, —C₃₋₇cycloalkyl, —CF₃, halogen, —OH, —CN, phenyl,pyrrolidinyl, azepanyl, —C₁₋₄hydroxyalkyl, —C₁₋₄alkoxy,(CH₃)₂N—(CH₂)₂—NH—, —SO₂—C₁₋₄alkyl, —C₀₋₄alkyl-N(C₀₋₅alkyl)(C₀₋₅alkyl),—C₀₋₄alkyl-N(C₃₋₆cycloalkyl)(C₀₋₅alkyl),—C₀₋₄alkyl-N(C₀₋₅alkyl)(C₁₋₄alkyloxyC₁₋₄alkyl),—N(C₀₋₅alkyl)-C₀₋₄alkyl-phenyl(C1-4alkoxyl)₀₋₃,—N(C₀₋₅alkyl)-C₀₋₄alkylthiaphenyl, dimethoxyphenyl-CH₂—NH—; any phenyloptionally substituted with 1–5 —OH, halogen, or C₁₋₄alkyl; any alkyloptionally substituted with 1–5 —OH or halogen; or the substituent takenwith a neighboring bond is ═O; or

A is pyrrolophenyl, imidazolophenyl, pyrazolophenyl, triazolophenyl,pyridinoimidazolyl, naphthyridinyl, tetrahydrocyclopentopyrazolyl,quinolinyl, pyrimidinopyrazololyl, benzothiazolyl, benzoimidazolyl,benzoxazolonyl, oxodihydrobenzoxazolyl, indolinonyl,oxadihydroquinolinyl, oxatetrahydroquinolinyl, or purinyl, eachoptionally substituted with 1–5 substituents, each substituentindependently is —C₁₋₄alkyl, —C₃₋₇cycloalkyl, —CF₃, halogen, —OH, or—CN;

B is aryl(CH₂)₀₋₃—O—(CH₂)₀₋₂—C(O)—, heteroaryl(CH₂)₁₋₃—O—(CH₂)₀₋₂—C(O)—,indanyl(CH₂)₀₋₃—O—(CH₂)₀₋₂—C(O)—, aryl(CH₂)₁₋₃—C(O)—(CH₂)₀₋₂—,aryl-cyclopropyl-C(O)—(CH₂)₀₋₂—, heteroaryl(CH₂)₁₋₃—C(O)—,aryl(CH₂)₁₋₃—, heteroaryl(CH₂)₁₋₃—, aryl(CH₂)₁₋₃—NH—C(O)—,aryl(CH₂)₁₋₃—NH—C(NCN)—, aryl(CH₂)₁₋₃—SO₂—,aryl(CH₂)₀₋₃—S—(CH₂)₀₋₂—C(O)—, or heteroaryl(CH₂)₃—SO₂— wherein any ofthe aryl or heteroaryl is optionally substituted by 1–5 substituents,each substituent independently is C₁₋₄alkyl, C₃₋₆cycloalkyl, C₁₋₄alkoxy,trifluoromethyl, phenyl, —O—C₁₋₄alkylphenyl, —S(O)—C₁₋₄alkyl, bromo,fluoro, chloro, or 2 substituents together form methylene dioxy; any(CH₂) optionally is substituted with C₁₋₂alkyl; or

B is

wherein the phenyl is optionally substituted by 1–3 substituents, eachsubstituent independently is C₁₋₄alkyl, C₃₋₆cycloalkyl, C₁₋₄alkoxy,trifluoromethyl, bromo, fluoro, or chloro; and

X is H, OH, F, C₁₋₄alkyl, C₁₋₄alkoxy, —N(C₀₋₅alkyl)(C₀₋₅alkyl), phenyl,or ═O.

In an embodiment of the first aspect, the compounds of this inventionare represented by Formula (I) or pharmaceutically acceptable saltsthereof, wherein

NonAr is a nonaromatic 6 membered ring containing 1 nitrogen ring atom,wherein the remaining ring atoms are carbon;

A is a phenyl optionally substituted with 1–5 substituents, eachsubstituent independently is C₁₋₄alkyl, C₃₋₇cycloalkyl, —CF₃, halogen,—OH, —CN, imidazolyl, —C₀₋₄alkyl-N(C₀₋₅alkyl)(C₀₋₅alkyl), —O—C₁₋₄alkyl,—C(O)—C₀₋₄alkyl, —C(O)—O—C₀₋₄alkyl, —O—C(O)—C₀₋₄alkyl,—O—C(O)—C₀₋₄alkylphenyl, —C₀₋₄alkyl-N(C₀₋₅alkyl)-C(O)—C₀₋₄alkyl,—C₀₋₄alkyl-N(C₀₋₅alkyl)-C(O)—O—C₀₋₄alkyl,—C₀₋₄alkyl-N(C₀₋₅alkyl)-C(O)—O—C₁₋₄alkyl, or —NHSO₂—C₁₋₄alkyl,—O—C₁₋₄alkylphenyl, or hydroxyiminoethyl; any alkyl optionallysubstituted with 1–6 —OH or halogen;

B is aryl(CH₂)₀₋₃—O—(CH₂)₀₋₂—C(O)—, heteroaryl(CH₂)₁₋₃—O—(CH₂)₀₋₂—C(O)—,indanyl(CH₂)₀₋₃—O—(CH₂)₀₋₂—C(O)—, aryl(CH₂)₁₋₃—C(O)—(CH₂)₀₋₂—,aryl-cyclopropyl-C(O)—(CH₂)₀₋₂—, heteroaryl(CH₂)₁₋₃—C(O)—,aryl(CH₂)₁₋₃—, heteroaryl(CH₂)₁₋₃—, aryl(CH₂)₁₋₃—NH—C(O)—,aryl(CH₂)₁₋₃—NH—C(NCN)—, aryl(CH₂)₁₋₃—SO₂—,aryl(CH₂)₀₋₃—S—(CH₂)₀₋₂—C(O)—, or heteroaryl(CH₂)₁₋₃—SO₂— wherein any ofthe aryl or heteroaryl is optionally substituted by 1–5 substituents,each substituent independently is C₁₋₄alkyl, C₃₋₆cycloalkyl, C₁₋₄alkoxy,trifluoromethyl, phenyl, —O—C₁₋₄alkylphenyl, —S(O)—C₁₋₄alkyl, bromo,fluoro, chloro, or 2 substituents together form methylene dioxy; any(CH₂) optionally is substituted with C₁₋₂alkyl; or

B is

wherein the phenyl is optionally substituted by 1–3 substituents, eachsubstituent independently is C₁₋₄alkyl, C₃₋₆cycloalkyl, C₁₋₄alkoxy,trifluoromethyl, bromo, fluoro, or chloro; and

X is H, OH, F, C₁₋₄alkyl, C₁₋₄alkoxy, —N(C₀₋₅alkyl)(C₀₋₅alkyl), phenyl,or ═O.

In another aspect of the first aspect, the compounds of this inventionare represented by Formula (I) or pharmaceutically acceptable saltsthereof, wherein

NonAr is a nonaromatic 6 membered ring containing 1 nitrogen ring atom,wherein the remaining ring atoms are carbon;

A is pyrrolyl, imidazolyl, pyrazolyl, triazolyl, thiophenyl, thiazolyl,thiadiazolyl, oxazolyl, or isoxazolyl, each optionally substituted with1–3 substituents, each substituent independently is —C₁₋₄alkyl,—C₃₋₇cycloalkyl, —CF₃, halogen, —OH, —CN, —C₁₋₄alkoxyl, phenyl,—C₀₋₄alkyl-N(C₀₋₅alkyl)(C₀₋₅alkyl), —C₁₋₄hydroxyalkyl;

B is aryl(CH₂)₀₋₃—O—(CH₂)₀₋₂—C(O)—, heteroaryl(CH₂)₁₋₃—O—(CH₂)₀₋₂—C(O)—,indanyl(CH₂)₀₋₃—O—(CH₂)₀₋₂—C(O)—, aryl(CH₂)₁₋₃—C(O)—(CH₂)₀₋₂—,aryl-cyclopropyl-C(O)—(CH₂)₀₋₂—, heteroaryl(CH₂)₁₋₃—C(O)—,aryl(CH₂)₁₋₃—, heteroaryl(CH₂)₁₋₃—, aryl(CH₂)₁₋₃—NH—C(O)—,aryl(CH₂)₁₋₃—NH—C(NCN)—, aryl(CH₂)₁₋₃—SO₂—,aryl(CH₂)₀₋₃—S—(CH₂)₀₋₂—C(O)—, or heteroaryl(CH₂)₁₋₃—SO₂— wherein any ofthe aryl or heteroaryl is optionally substituted by 1–5 substituents,each substituent independently is C₁₋₄alkyl, C₃₋₆cycloalkyl, C₁₋₄alkoxy,trifluoromethyl, phenyl, —O—C₁₋₄alkylphenyl, —S(O)—C₁₋₄alkyl, bromo,fluoro, chloro, or 2 substituents together form methylene dioxy; any(CH₂) optionally is substituted with C₁₋₂alkyl; or

B is

wherein the phenyl is optionally substituted by 1–3 substituents, eachsubstituent independently is C₁₋₄alkyl, C₃₋₆cycloalkyl, C₁₋₄alkoxy,trifluoromethyl, bromo, fluoro, or chloro; and

X is H, OH, F, C₁₋₄alkyl, C₁₋₄alkoxy, —N(C₀₋₅alkyl)(C₀₋₅alkyl), phenyl,or ═O.

In still another embodiment of the first aspect, the compounds of thisinvention are represented by Formula (I) or pharmaceutically acceptablesalts thereof, wherein

NonAr is a nonaromatic 6 membered ring containing 1 nitrogen ring atom,wherein the remaining ring atoms are carbon;

A is pyridyl, pyradazinyl, pyrimidinyl, or pyrazinyl, each optionallysubstituted with 1–5 substituents; each substituent independently is—C₁₋₄alkyl, —C₃₋₇cycloalkyl, —CF₃, halogen, —OH, —CN, phenyl,pyrrolidinyl, azepanyl, —C₁₋₄hydroxyalkyl, —C₄alkoxy,(CH₃)₂N—(CH₂)₂—NH—, —SO₂—C₁₋₄alkyl, —C₀₋₄alkyl-N(C₀₋₅alkyl)(C₀₋₅alkyl),—CO₄alkyl-N(C₃₋₆cycloalkyl)(C₀₋₅alkyl),—C₀₋₄alkyl-N(C₀₋₅alkyl)(C₁₋₄alkyloxyC₁₋₄alkyl),—N(C₀₋₅alkyl)-C₀₋₄alkyl-phenyl(C1–4alkoxyl)₀₋₃,—N(C₀₋₅alkyl)-C₀₋₄alkylthiaphenyl, dimethoxyphenyl-CH₂—NH—; any phenyloptionally substituted with 1–5 —OH, halogen, or C₁₋₄alkyl; any alkyloptionally substituted with 1–5 —OH or halogen; or the substituent takenwith a neighboring bond is ═O;

B is aryl(CH₂)₀₋₃—O—(CH₂)₀₋₂—C(O)—, heteroaryl(CH₂)₁₋₃—O—(CH₂)₀₋₂—C(O)—,indanyl(CH₂)₀₋₃—O—(CH₂)₀₋₂—C(O)—, aryl(CH₂)₁₋₃—C(O)—(CH₂)₀₋₂—,aryl-cyclopropyl-C(O)—(CH₂)₀₋₂—, heteroaryl(CH₂)₁₋₃—C(O)—,aryl(CH₂)₁₋₃—, heteroaryl(CH₂)₁₋₃—, aryl(CH₂)₁₋₃—NH—C(O)—,aryl(CH₂)₁₋₃—NH—C(NCN)—, aryl(CH₂)₁₋₃—SO₂—,aryl(CH₂)₀₋₃—S—(CH₂)₀₋₂—C(O)—, or heteroaryl(CH₂)₁₋₃—SO₂— wherein any ofthe aryl or heteroaryl is optionally substituted by 1–5 substituents,each substituent independently is C₁₋₄alkyl, C₃₋₆cycloalkyl, C₁₋₄alkoxy,trifluoromethyl, phenyl, —O—C₁₋₄alkylphenyl, —S(O)—C₁₋₄alkyl, bromo,fluoro, chloro, or 2 substituents together form methylene dioxy; any(CH₂) optionally is substituted with C₁₋₂alkyl; or

B is

wherein the phenyl is optionally substituted by 1–3 substituents, eachsubstituent independently is C₁₋₄alkyl, C₃₋₆cycloalkyl, C₁₋₄alkoxy,trifluoromethyl, bromo, fluoro, or chloro; and

X is H, OH, F, C₁₋₄alkyl, C₁₋₄alkoxy, —N(C₀₋₅alkyl)(C₀₋₅alkyl), phenyl,or ═O.

In another embodiment of the first aspect, the compounds of thisinvention are represented by Formula (I) or pharmaceutically acceptablesalts thereof, wherein

NonAr is a nonaromatic 6 membered ring containing 1 nitrogen ring atom,wherein the remaining ring atoms are carbon;

A is pyrrolophenyl, imidazolophenyl, pyrazolophenyl, triazolophenyl,pyridinoimidazolyl, naphthyridinyl, tetrahydrocyclopentopyrazolyl,quinolinyl, pyrimidinopyrazololyl, benzothiazolyl, benzoimidazolyl,benzoxazolonyl, oxodihydrobenzoxazolyl, indolinonyl,oxadihydroquinolinyl, oxatetrahydroquinolinyl, or purinyl, eachoptionally substituted with 1–5 substituents, each substituentindependently is —C₁₋₄alkyl, —C₃₋₇cycloalkyl, —CF₃, halogen, —OH, or—CN;

B is aryl(CH₂)₀₋₃—O—(CH₂)₀₋₂—C(O)—, heteroaryl(CH₂)₁₋₃—O—(CH₂)₀₋₂—C(O)—,indanyl(CH₂)₀₋₃—O—(CH₂)₀₋₂—C(O)—, aryl(CH₂)₁₋₃—C(O)—(CH₂)₀₋₂—,aryl-cyclopropyl-C(O)—(CH₂)₀₋₂—, heteroaryl(CH₂)₁₋₃—C(O)—,aryl(CH₂)₁₋₃—, heteroaryl(CH₂)₁₋₃—, aryl(CH₂)₁₋₃—NH—C(O)—,aryl(CH₂)₁₋₃—NH—C(NCN)—, aryl(CH₂)₁₋₃—SO₂—,aryl(CH₂)₀₋₃—S—(CH₂)₀₋₂—C(O)—, or heteroaryl(CH₂)₁₋₃—SO₂— wherein any ofthe aryl or heteroaryl is optionally substituted by 1–5 substituents,each substituent independently is C₁₋₄alkyl, C₃₋₆cycloalkyl, C₁₋₄alkoxy,trifluoromethyl, phenyl, —O—C₁₋₄alkylphenyl, —S(O)—C₁₋₄alkyl, bromo,fluoro, chloro, or 2 substituents together form methylene dioxy; any(CH₂) optionally is substituted with C₁₋₂alkyl; or

B is

wherein the phenyl is optionally substituted by 1–3 substituents, eachsubstituent independently is C₁₋₄alkyl, C₃₋₆cycloalkyl, C₁₋₄alkoxy,trifluoromethyl, bromo, fluoro, or chloro; and

X is H, OH, F, C₁₋₄alkyl, C₁₋₄alkoxy, —N(C₀₋₅alkyl)(C₀₋₅alkyl), phenyl,or ═O.

In a second aspect, the compounds of this invention are represented byFormula (I) or pharmaceutically acceptable salts thereof, wherein

NonAr is a nonaromatic 5 membered ring containing 1 nitrogen ring atom,wherein the remaining ring atoms are carbon;

A is a phenyl optionally substituted with 1–5 substituents, eachsubstituent independently is C₁₋₄alkyl, C₃₋₇cycloalkyl, —CF₃, halogen,—OH, —CN, imidazolyl, —C₀₋₄alkyl-N(C₀₋₅alkyl)(C₀₋₅alkyl), —O—C₁₋₄alkyl,—C(O)—C₀₋₄alkyl, —C(O)—O—C₀₋₄alkyl, —O—C(O)—C₀₋₄alkyl,—O—C(O)—C₀₋₄alkylphenyl, —C₀₋₄alkyl-N(C₀₋₅alkyl)-C(O)—C₀₋₄alkyl,—C₀₋₄alkyl-N(C₀₋₅alkyl)-C(O)—O—C₀₋₄alkyl,—C₀₋₄alkyl-N(C₀₋₅alkyl)-C(O)—O—C₁₋₄alkyl, or —NHSO₂—C₁₋₄alkyl,—O—C₁₋₄alkylphenyl, or hydroxyiminoethyl; any alkyl optionallysubstituted with 1–6 —OH or halogen; or

A is pyrrolyl, imidazolyl, pyrazolyl, triazolyl, thiophenyl, thiazolyl,thiadiazolyl,oxazolyl, or isoxazolyl, each optionally substituted with1–3 substituents, each substituent independently is —C₁₋₄alkyl,—C₃₋₇cycloalkyl, —CF₃, halogen, —OH, —CN, —C₁₋₄alkoxyl, phenyl,—C₀₋₄alkyl-N(C₀₋₅alkyl)(C₀₋₅alkyl), —C₁₋₄hydroxyalkyl; or

A is pyridyl, pyradazinyl, pyrimidinyl, or pyrazinyl, each optionallysubstituted with 1–5 substituents; each substituent independently is—C₁₋₄alkyl, —C₃₋₇cycloalkyl, —CF₃, halogen, —OH, —CN, phenyl,pyrrolidinyl, azepanyl, —C₁₋₄hydroxyalkyl, —C₁₋₄alkoxy,(CH₃)₂N—(CH₂)₂—NH—, —SO₂—C₁₋₄alkyl, —C₀₋₄alkyl-N(C₀₋₅alkyl)(C₀₋₅alkyl),—C₀₋₄alkyl-N(C₃₋₆cycloalkyl)(C₀₋₅alkyl),—C₀₋₄alkyl-N(C₀₋₅alkyl)(C₁₋₄alkyloxyC₁₋₄alkyl),—N(C₀₋₅alkyl)-C₀₋₄alkyl-phenyl(C1–4alkoxyl)₀₋₃,—N(C₀₋₅alkyl)-C₀₋₄alkylthiaphenyl, dimethoxyphenyl-CH₂—NH—; any phenyloptionally substituted with 1–5 —OH, halogen, or C₁₋₄alkyl; any alkyloptionally substituted with 1–5 —OH or halogen; or the substituent takenwith a neighboring bond is ═O; or

A is pyrrolophenyl, imidazolophenyl, pyrazolophenyl, triazolophenyl,pyridinoimidazolyl, naphthyridinyl, tetrahydrocyclopentopyrazolyl,quinolinyl, pyrimidinopyrazololyl, benzothiazolyl, benzoimidazolyl,benzoxazolonyl, oxodihydrobenzoxazolyl, indolinonyl,oxadihydroquinolinyl, oxatetrahydroquinolinyl, or purinyl, eachoptionally substituted with 1–5 substituents, each substituentindependently is —C₁₋₄alkyl, —C₃₋₇cycloalkyl, —CF₃, halogen, —OH, or—CN;

B is aryl(CH₂)₀₋₃—O—(CH₂)₀₋₂—C(O)—, heteroaryl(CH₂)₁₋₃—O—(CH₂)₀₋₂—C(O)—,indanyl(CH₂)₀₋₃—O—(CH₂)₀₋₂—C(O)—, aryl(CH₂)₁₋₃—C(O)—(CH₂)₀₋₂—,aryl-cyclopropyl-C(O)—(CH₂)₀₋₂—, heteroaryl(CH₂)₁₋₃—C(O)—,aryl(CH₂)₁₋₃—, heteroaryl(CH₂)₁₋₃—, aryl(CH₂)₁₋₃—NH—C(O)—,aryl(CH₂)₁₋₃—NH—C(NCN)—, aryl(CH₂)₁₋₃—SO₂—,aryl(CH₂)₀₋₃—S—(CH₂)₀₋₂—C(O)—, or heteroaryl(CH₂)₁₋₃—SO₂— wherein any ofthe aryl or heteroaryl is optionally substituted by 1–5 substituents,each substituent independently is C₁₋₄alkyl, C₃₋₆cycloalkyl, C₁₋₄alkoxy,trifluoromethyl, phenyl, —O—C₁₋₄alkylphenyl, —S(O)—C₁₋₄alkyl, bromo,fluoro, chloro, or 2 substituents together form methylene dioxy; any(CH₂) optionally is substituted with C₁₋₂alkyl; or

B is

wherein the phenyl is optionally substituted by 1–3 substituents, eachsubstituent independently is C₁₋₄alkyl, C₃₋₆cycloalkyl, C₁₋₄alkoxy,trifluoromethyl, bromo, fluoro, or chloro; and

X is H, OH, F, C₁₋₄alkyl, C₁₋₄alkoxy, —N(C₀₋₅alkyl)(C₀₋₅alkyl), phenyl,or ═O.

In an embodiment of the second aspect, the compounds of this inventionare represented by Formula (I) or pharmaceutically acceptable saltsthereof, wherein

NonAr is a nonaromatic 5 membered ring containing 1 nitrogen ring atom,wherein the remaining ring atoms are carbon;

A is a phenyl optionally substituted with 1–5 substituents, eachsubstituent independently is C₁₋₄alkyl, C₃₋₇cycloalkyl, —CF₃, halogen,—OH, —CN, imidazolyl, —C₀₋₄alkyl-N(C₀₋₅alkyl)(C₀₋₅alkyl), —O—C₁₋₄alkyl,—C(O)—C₀₋₄alkyl, —C(O)—O—C₀₋₄alkyl, —O—C(O)—C₀₋₄alkyl,—O—C(O)—C₀₋₄alkylphenyl, —C₀₋₄alkyl-N(C₀₋₅alkyl)-C(O)—C₀₋₄alkyl,—C₀₋₄alkyl-N(C₀₋₅alkyl)-C(O)—O—C₀₋₄alkyl,—C₀₋₄alkyl-N(C₀₋₅alkyl)-C(O)—O—C₁₋₄alkyl, or —NHSO₂—C₁₋₄alkyl,—O—C₁₋₄alkylphenyl, or hydroxyiminoethyl; any alkyl optionallysubstituted with 1–6 —OH or halogen;

B is aryl(CH₂)₀₋₃—O—(CH₂)₀₋₂—C(O)—, heteroaryl(CH₂)₁₋₃—O—(CH₂)₀₋₂—C(O)—,indanyl(CH₂)₀₋₃—O—(CH₂)₀₋₂—C(O)—, aryl(CH₂)₁₋₃—C(O)—(CH₂)₀₋₂—,aryl-cyclopropyl-C(O)—(CH₂)₀₋₂—, heteroaryl(CH₂)₁₋₃—C(O)—,aryl(CH₂)₁₋₃—, heteroaryl(CH₂)₁₋₃—, aryl(CH₂)₁₋₃—NH—C(O)—,aryl(CH₂)₁₋₃—NH—C(NCN)—, aryl(CH₂)₁₋₃—SO₂—,aryl(CH₂)₀₋₃—S—(CH₂)₀₋₂—C(O)—, or heteroaryl(CH₂)₁₋₃—SO₂— wherein any ofthe aryl or heteroaryl is optionally substituted by 1–5 substituents,each substituent independently is C₁₋₄alkyl, C₃₋₆cycloalkyl, C₁₋₄alkoxy,trifluoromethyl, phenyl, —O—C₁₋₄alkylphenyl, —S(O)—C₁₋₄alkyl, bromo,fluoro, chloro, or 2 substituents together form methylene dioxy; any(CH₂) optionally is substituted with C₁₋₂alkyl; or

B is

wherein the phenyl is optionally substituted by 1–3 substituents, eachsubstituent independently is C₁₋₄alkyl, C₃₋₆cycloalkyl, C₁₋₄alkoxy,trifluoromethyl, bromo, fluoro, or chloro; and

X is H, OH, F, C₁₋₄alkyl, C₁₋₄alkoxy, —N(C₀₋₅alkyl)(C₀₋₅alkyl), phenyl,or ═O.

In a third aspect, the compounds of this invention are represented byFormula (I) or pharmaceutically acceptable salts thereof, wherein

NonAr is a nonaromatic 6 membered ring containing 2 nitrogen ring atoms,wherein the remaining ring atoms are carbon;

A is a phenyl optionally substituted with 1–5 substituents, eachsubstituent independently is C₁₋₄alkyl, C₃₋₇cycloalkyl, —CF₃, halogen,—OH, —CN, imidazolyl, —C₀₋₄alkyl-N(C₀₋₅alkyl)(C₀₋₅alkyl), —O—C₁₋₄alkyl,—C(O)—C₀₋₄alkyl, —C(O)—O—C₀₋₄alkyl, —O—C(O)—C₀₋₄alkyl,—O—C(O)—C₀₋₄alkylphenyl, —C₀₋₄alkyl-N(C₀₋₅alkyl)—C(O)—C₀₋₄alkyl,—C₀₋₄alkyl-N(C₀₋₅alkyl)-C(O)—O—C₀₋₄alkyl,—C₀₋₄alkyl-N(C₀₋₅alkyl)-C(O)—O—C₁₋₄alkyl, or —NHSO₂—C₁₋₄alkyl,—O—C₁₋₄alkylphenyl, or hydroxyiminoethyl; any alkyl optionallysubstituted with 1–6 —OH or halogen; or

A is pyrrolyl, imidazolyl, pyrazolyl, triazolyl, thiophenyl, thiazolyl,thiadiazolyl, oxazolyl, or isoxazolyl, each optionally substituted with1–3 substituents, each substituent independently is —C₁₋₄alkyl,—C₃₋₇cycloalkyl, —CF₃, halogen, —OH, —CN, —C₁₋₄alkoxyl, phenyl,—C₀₋₄alkyl-N(C₀₋₅alkyl)(C₀₋₅alkyl), —C₁₋₄hydroxyalkyl; or

A is pyridyl, pyradazinyl, pyrimidinyl, or pyrazinyl, each optionallysubstituted with 1–5 substituents; each substituent independently is—C₁₋₄alkyl, —C₃₋₇cycloalkyl, —CF₃, halogen, —OH, —CN, phenyl,pyrrolidinyl, azepanyl, —C₁₋₄hydroxyalkyl, —C₁₋₄alkoxy,(CH₃)₂N—(CH₂)₂—NH—, —SO₂—C₁₋₄alkyl, —C₀₋₄alkyl-N(C₀₋₅alkyl)(C₀₋₅alkyl),—C₀₋₄alkyl-N(C₃₋₆cycloalkyl)(C₀₋₅alkyl),—C₀₋₄alkyl-N(C₀₋₅alkyl)(C₁₋₄alkyloxyC₁₋₄alkyl),—N(C₀₋₅alkyl)-C₀₋₄alkyl-phenyl(C1–4alkoxyl)₀₋₃,—N(C₀₋₅alkyl)-C₀₋₄alkylthiaphenyl, dimethoxyphenyl-CH₂—NH—; any phenyloptionally substituted with 1–5 —OH, halogen, or C₁₋₄alkyl; any alkyloptionally substituted with 1–5 —OH or halogen; or the substituent takenwith a neighboring bond is ═O; or

A is pyrrolophenyl, imidazolophenyl, pyrazolophenyl, triazolophenyl,pyridinoimidazolyl, naphthyridinyl, tetrahydrocyclopentopyrazolyl,quinolinyl, pyrimidinopyrazololyl, benzothiazolyl, benzoimidazolyl,benzoxazolonyl, oxodihydrobenzoxazolyl, indolinonyl,oxadihydroquinolinyl, oxatetrahydroquinolinyl, or purinyl, eachoptionally substituted with 1–5 substituents, each substituentindependently is —C₁₋₄alkyl, —C₃₋₇cycloalkyl, —CF₃, halogen, —OH, or—CN;

B is aryl(CH₂)₀₋₃—O—(CH₂)₀₋₂—C(O)—, heteroaryl(CH₂)₁₋₃—O—(CH₂)₀₋₂—C(O)—,indanyl(CH₂)₀₋₃—O—(CH₂)₀₋₂—C(O)—, aryl(CH₂)₁₋₃—C(O)—(CH₂)₀₋₂—,aryl-cyclopropyl-C(O)—(CH₂)₀₋₂—, heteroaryl(CH₂)₁₋₃—C(O)—,aryl(CH₂)₁₋₃—, heteroaryl(CH₂)₁₋₃—, aryl(CH₂)₁₋₃—NH—C(O)—,aryl(CH₂)₁₋₃—NH—C(NCN)—, aryl(CH₂)₁₋₃—SO₂—,aryl(CH₂)₀₋₃—S—(CH₂)₀₋₂—C(O)—, or heteroaryl(CH₂)₁₋₃—SO₂— wherein any ofthe aryl or heteroaryl is optionally substituted by 1–5 substituents,each substituent independently is C₁₋₄alkyl, C₃₋₆cycloalkyl, C₁₋₄alkoxy,trifluoromethyl, phenyl, —O—C₁₋₄alkylphenyl, —S(O)—C₁₋₄alkyl, bromo,fluoro, chloro, or 2 substituents together form methylene dioxy; any(CH₂) optionally is substituted with C₁₋₂alkyl; or

B is

wherein the phenyl is optionally substituted by 1–3 substituents, eachsubstituent independently is C₁₋₄alkyl, C₃₋₆cycloalkyl, C₁₋₄alkoxy,trifluoromethyl, bromo, fluoro, or chloro; and

X is H, OH, F, C₁₋₄alkyl, C₁₋₄alkoxy, —N(C₀₋₅alkyl)(C₀₋₅alkyl), phenyl,or ═O.

In an embodiment of the third aspect, the compounds of this inventionare represented by Formula (I) or pharmaceutically acceptable saltsthereof, wherein

NonAr is a nonaromatic 6 membered ring containing 2 nitrogen ring atoms,wherein the remaining ring atoms are carbon;

A is a phenyl optionally substituted with 1–5 substituents, eachsubstituent independently is C₁₋₄alkyl, C₃₋₇cycloalkyl, —CF₃, halogen,—OH, —CN, imidazolyl, —C₀₋₄alkyl-N(C₀₋₅alkyl)(C₀₋₅alkyl), —O—C₁₋₄alkyl,—C(O)—C₀₋₄alkyl, —C(O)—O—C₀₋₄alkyl, —O—C(O)—C₀₋₄alkyl,—O—C(O)—C₀₋₄alkylphenyl, —C₀₋₄alkyl-N(C₀₋₅alkyl)-C(O)—C₀₋₄alkyl,—C₀₋₄alkyl-N(C₀₋₅alkyl)-C(O)—O—C₀₋₄alkyl,—C₀₋₄alkyl-N(C₀₋₅alkyl)-C(O)—O—C₁₋₄alkyl, or —NHSO₂—C₁₋₄alkyl,—O—C₁₋₄alkylphenyl, or hydroxyiminoethyl; any alkyl optionallysubstituted with 1–6 —OH or halogen;

B is aryl(CH₂)₀₋₃—O—(CH₂)₀₋₂—C(O)—, heteroaryl(CH₂)₁₋₃—O—(CH₂)₀₋₂—C(O)—,indanyl(CH₂)₀₋₃—O—(CH₂)₀₋₂—C(O)—, aryl(CH₂)₁₋₃—C(O)—(CH₂)₀₋₂—,aryl-cyclopropyl-C(O)—(CH₂)₀₋₂—, heteroaryl(CH₂)₁₋₃—C(O)—,aryl(CH₂)₁₋₃—, heteroaryl(CH₂)₁₋₃—, aryl(CH₂)₁₋₃—NH—C(O)—,aryl(CH₂)₁₋₃—NH—C(NCN)—, aryl(CH₂)₁₋₃—SO₂—,aryl(CH₂)₀₋₃—S—(CH₂)₀₋₂—C(O)—, or heteroaryl(CH₂)₁₋₃—SO₂— wherein any ofthe aryl or heteroaryl is optionally substituted by 1–5 substituents,each substituent independently is C₁₋₄alkyl, C₃₋₆cycloalkyl, C₁₋₄alkoxy,trifluoromethyl, phenyl, —O—C₁₋₄alkylphenyl, —S(O)—C₁₋₄alkyl, bromo,fluoro, chloro, or 2 substituents together form methylene dioxy; any(CH₂) optionally is substituted with C₁₋₂alkyl; or

B is

wherein the phenyl is optionally substituted by 1–3 substituents, eachsubstituent independently is C₁₋₄alkyl, C₃₋₆cycloalkyl, C₁₋₄alkoxy,trifluoromethyl, bromo, fluoro, or chloro; and

X is H, OH, F, C₁₋₄alkyl, C₁₋₄alkoxy, —N(C₀₋₅alkyl)(C₀₋₅alkyl), phenyl,or ═O.

In a fourth aspect, the compounds of this invention are represented byFormula (I) or pharmaceutically acceptable salts thereof, wherein

NonAr is a nonaromatic 6 membered ring containing 1 nitrogen ring atomand 1 oxygen ring atom, wherein the remaining ring atoms are carbon;

A is a phenyl optionally substituted with 1–5 substituents, eachsubstituent independently is C₁₋₄alkyl, C₃₋₇cycloalkyl, —CF₃, halogen,—OH, —CN, imidazolyl, —C₀₋₄alkyl-N(C₀₋₅alkyl)(C₀₋₅alkyl), —O—C₁₋₄alkyl,—C(O)—C₀₋₄alkyl, —C(O)—O—C₀₋₄alkyl, —O—C(O)—C₀₋₄alkyl,—O—C(O)—C₀₋₄alkylphenyl, —C₀₋₄alkyl-N(C₀₋₅alkyl)-C(O)—C₀₋₄alkyl,—C₀₋₄alkyl-N(C₀₋₅alkyl)-C(O)—O—C₀₋₄alkyl,—C₀₋₄alkyl-N(C₀₋₅alkyl)-C(O)—O—C₁₋₄alkyl, or —NHSO₂—C₁₋₄alkyl,—O—C₁₋₄alkylphenyl, or hydroxyiminoethyl; any alkyl optionallysubstituted with 1–6 —OH or halogen; or

A is pyrrolyl, imidazolyl, pyrazolyl, triazolyl, thiophenyl, thiazolyl,thiadiazolyl, oxazolyl, or isoxazolyl, each optionally substituted with1–3 substituents, each substituent independently is —C₁₋₄alkyl,—C₃₋₇cycloalkyl, —CF₃, halogen, —OH, —CN, —C₁₋₄alkoxyl, phenyl,—C₀₋₄alkyl-N(C₀₋₅alkyl)(C₀₋₅alkyl), —C₁₋₄hydroxyalkyl; or

A is pyridyl, pyradazinyl, pyrimidinyl, or pyrazinyl, each optionallysubstituted with 1–5 substituents; each substituent independently is—C₁₋₄alkyl, —C₃₋₇cycloalkyl, —CF₃, halogen, —OH, —CN, phenyl,pyrrolidinyl, azepanyl, —C₁₋₄hydroxyalkyl, —C₁₋₄alkoxy,(CH₃)₂N—(CH₂)₂—NH—, —SO₂—C₁₋₄alkyl, —C₀₋₄alkyl-N(C₀₋₅alkyl)(C₀₋₅alkyl),—C₀₋₄alkyl-N(C₃₋₆cycloalkyl)(C₀₋₅alkyl),—C₀₋₄alkyl-N(C₀₋₅alkyl)(C₁₋₄alkyloxyC₁₋₄alkyl),—N(C₀₋₅alkyl)-C₀₋₄alkyl-phenyl(C1-4alkoxyl)₀₋₃,—N(C₀₋₅alkyl)-C₀₋₄alkylthiaphenyl, dimethoxyphenyl-CH₂—NH—; any phenyloptionally substituted with 1–5 —OH, halogen, or C₁₋₄alkyl; any alkyloptionally substituted with 1–5 —OH or halogen; or the substituent takenwith a neighboring bond is ═O; or

A is pyrrolophenyl, imidazolophenyl, pyrazolophenyl, triazolophenyl,pyridinoimidazolyl, naphthyridinyl, tetrahydrocyclopentopyrazolyl,quinolinyl, pyrimidinopyrazololyl, benzothiazolyl, benzoimidazolyl,benzoxazolonyl, oxodihydrobenzoxazolyl, indolinonyl,oxadihydroquinolinyl, oxatetrahydroquinolinyl, or purinyl, eachoptionally substituted with 1–5 substituents, each substituentindependently is —C₁₋₄alkyl, —C₃₋₇cycloalkyl, —CF₃, halogen, —OH, or—CN;

B is aryl(CH₂)₀₋₃—O—(CH₂)₀₋₂—C(O)—, heteroaryl(CH₂)₁₋₃—O—(CH₂)₀₋₂—C(O)—,indanyl(CH₂)₀₋₃—O—(CH₂)₀₋₂—C(O)—, aryl(CH₂)₁₋₃—C(O)—(CH₂)₀₋₂—,aryl-cyclopropyl-C(O)—(CH₂)₀₋₂—, heteroaryl(CH₂)₁₋₃—C(O)—,aryl(CH₂)₁₋₃—, heteroaryl(CH₂)₁₋₃—, aryl(CH₂)₁₋₃—NH—C(O)—,aryl(CH₂)₁₋₃—NH—C(NCN)—, aryl(CH₂)₁₋₃—SO₂—,aryl(CH₂)₀₋₃—S—(CH₂)₀₋₂—C(O)—, or heteroaryl(CH₂)₁₋₃—SO₂— wherein any ofthe aryl or heteroaryl is optionally substituted by 1–5 substituents,each substituent independently is C₁₋₄alkyl, C₃₋₆cycloalkyl, C₁₋₄alkoxy,trifluoromethyl, phenyl, —O—C₁₋₄alkylphenyl, —S(O)—C₁₋₄alkyl, bromo,fluoro, chloro, or 2 substituents together form methylene dioxy; any(CH₂) optionally is substituted with C₁₋₂alkyl; or

B is

wherein the phenyl is optionally substituted by 1–3 substituents, eachsubstituent independently is C₁₋₄alkyl, C₃₋₆cycloalkyl, C₁₋₄alkoxy,trifluoromethyl, bromo, fluoro, or chloro; and

X is H, OH, F, C₁₋₄alkyl, C₁₋₄alkoxy, —N(C₀₋₅alkyl)(C₀₋₅alkyl), phenyl,or ═O.

In an embodiment of the fourth aspect, the compounds of this inventionare represented by Formula (I) or pharmaceutically acceptable saltsthereof, wherein

NonAr is a nonaromatic 6 membered ring containing 1 nitrogen ring atomand 1 oxygen ring atom, wherein the remaining ring atoms are carbon;

A is a phenyl optionally substituted with 1–5 substituents, eachsubstituent independently is C₁₋₄alkyl, C₃₋₇cycloalkyl, —CF₃, halogen,—OH, —CN, imidazolyl, —C₀₋₄alkyl-N(C₀₋₅alkyl)(C₀₋₅alkyl), —O—C₁₋₄alkyl,—C(O)—C₀₋₄alkyl, —C(O)—O—C₀₋₄alkyl, —O—C(O)—C₀₋₄alkyl,—O—C(O)—C₀₋₄alkylphenyl, —C₀₋₄alkyl-N(C₀₋₅alkyl)-C(O)—C₀₋₄alkyl,—C₀₋₄alkyl-N(C₀₋₅alkyl)-C(O)—O—C₀₋₄alkyl,—C₀₋₄alkyl-N(C₀₋₅alkyl)-C(O)—O—C₁₋₄alkyl, or —NHSO₂-C₁₋₄alkyl,—O—C₁₋₄alkylphenyl, or hydroxyiminoethyl; any alkyl optionallysubstituted with 1–6 —OH or halogen;

B is aryl(CH₂)₀₋₃—O—(CH₂)₀₋₂—C(O)—, heteroaryl(CH₂)₁₋₃—O—(CH₂)₀₋₂—C(O)—,indanyl(CH₂)₀₋₃—O—(CH₂)₀₋₂—C(O)—, aryl(CH₂)₁₋₃—C(O)—(CH₂)₀₋₂—,aryl-cyclopropyl-C(O)—(CH₂)₀₋₂—, heteroaryl(CH₂)₁₋₃—C(O)—,aryl(CH₂)₁₋₃—, heteroaryl(CH₂)₁₋₃—, aryl(CH₂)₁₋₃—NH—C(O)—,aryl(CH₂)₁₋₃—NH—C(NCN)—, aryl(CH₂)₁₋₃—SO₂—,aryl(CH₂)₀₋₃—S—(CH₂)₀₋₂—C(O)—, or heteroaryl(CH₂)₁₋₃—SO₂— wherein any ofthe aryl or heteroaryl is optionally substituted by 1–5 substituents,each substituent independently is C₁₋₄alkyl, C₃₋₆cycloalkyl, C₁₋₄alkoxy,trifluoromethyl, phenyl, —O—C₁₋₄alkylphenyl, —S(O)—C₁₋₄alkyl, bromo,fluoro, chloro, or 2 substituents together form methylene dioxy; any(CH₂) optionally is substituted with C₁₋₂alkyl; or

B is

wherein the phenyl is optionally substituted by 1–3 substituents, eachsubstituent independently is C₁₋₄alkyl, C₃₋₆cycloalkyl, C₁₋₄alkoxy,trifluoromethyl, bromo, fluoro, or chloro; and

X is H, OH, F, C₁₋₄alkyl, C₁₋₄alkoxy, —N(C₀₋₅alkyl)(C₀₋₅alkyl), phenyl,or ═O.

The term “cycloalkyl” means carbocycles containing no heteroatoms, andincludes mono-, bi- and tricyclic saturated carbocycles, as well asfused ring systems. Such fused ring systems can include one ring that ispartially or fully unsaturated such as a benzene ring to form fused ringsystems such as benzofused carbocycles. Cycloalkyl includes such fusedring systems as spirofused ring systems. Examples of cycloalkyl includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, decahydronaphthalenyl,adamantanyl, indanyl, indenyl, fluorenyl, 1,2,3,4-tetrahydronaphthalenyland the like. Similarly, “cycloalkenyl” means carbocycles containing noheteroatoms and at least one non-aromatic C—C double bond, and includemono-, bi- and tricyclic partially saturated carbocycles, as well asbenzofused cycloalkenes. Examples of cycloalkenyl include cyclohexenyl,indenyl, and the like.

The term “cycloalkyloxy” unless specifically stated otherwise includes acycloalkyl group connected to the oxy connecting atom.

The term “alkoxy” unless specifically stated otherwise includes an alkylgroup connected to the oxy connecting atom.

The term “aryl” unless specifically stated otherwise includes multiplering systems as well as single ring systems such as, for example, phenylor naphthyl.

The term “aryloxy” unless specifically stated otherwise includesmultiple ring systems as well as single ring systems such as, forexample, phenyl or naphthyl, connected through the oxy connecting atomto the connecting site.

The term “C₀–C₆alkyl” includes alkyls containing 6, 5, 4, 3, 2, 1, or nocarbon atoms. An alkyl with no carbon atoms is a hydrogen atomsubstituent when the alkyl is a terminus moiety. An alkyl with no carbonatoms is a direct bond when the alkyl is a bridging moiety.

The term “hetero” unless specifically stated otherwise includes one ormore O, S, or N atoms. For example, heterocycloalkyl and heteroarylinclude ring systems that contain one or more O, S, or N atoms in thering, including mixtures of such atoms. The heteroatoms replace ringcarbon atoms. Thus, for example, a heterocycloC₅alkyl is a five memberedring containing from 5 to no carbon atoms.

Examples of heteroaryl include, for example, pyridinyl, quinolinyl,isoquinolinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinoxalinyl, furyl,benzofuryl, dibenzofuryl, thienyl, benzothienyl, pyrrolyl, indolyl,pyrazolyl, indazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,imidazolyl, benzimidazolyl, oxadiazolyl, thiadiazolyl, triazolyl,tetrazolyl.

The term “heteroaryloxy” unless specifically stated otherwise describesa heteroaryl group connected through an oxy connecting atom to theconnecting site.

Examples of heteroaryl(C₁₋₆)alkyl include, for example, furylmethyl,furylethyl, thienylmethyl, thienylethyl, pyrazolylmethyl,oxazolylmethyl, oxazolylethyl, isoxazolylmethyl, thiazolylmethyl,thiazolylethyl, imidazolylmethyl, imidazolylethyl, benzimidazolylmethyl,oxadiazolylmethyl, oxadiazolylethyl, thiadiazolylmethyl,thiadiazolylethyl, triazolylmethyl, triazolylethyl, tetrazolylmethyl,tetrazolylethyl, pyridinylmethyl, pyridinylethyl, pyridazinylmethyl,pyrimidinylmethyl, pyrazinylmethyl, quinolinylmethyl,isoquinolinylmethyl and quinoxalinylmethyl.

Examples of heterocycloC₃₋₇alkyl include, for example, azetidinyl,pyrrolidinyl, piperidinyl, perhydroazepinyl, piperazinyl, morpholinyl,tetrahydrofuranyl, imidazolinyl, pyrolidin-2-one, piperidin-2-one, andthiomorpholinyl.

The term “N-heterocycloC₄₋₇alkyl” describes nonaryl heterocycliccompounds having 3–6 carbon atoms and one nitrogen atom forming thering. Examples include azetidinyl, pyrrolidinyl, piperidinyl, andperhydroazepinyl.

Examples of aryl(C₁₋₆)alkyl include, for example, phenyl(C₁₋₆)alkyl, andnaphthyl(C₁₋₆)alkyl.

Examples of heterocycloC₃₋₇alkylcarbonyl(C₁₋₆)alkyl include, forexample, azetidinyl carbonyl(C₁₋₆)alkyl, pyrrolidinylcarbonyl(C₁₋₆)alkyl, piperidinyl carbonyl(C₁₋₆)alkyl, piperazinylcarbonyl(C₁₋₆)alkyl, morpholinyl carbonyl(C₁₋₆)alkyl, andthiomorpholinyl carbonyl(C₁₋₆)alkyl.

The term “amine” unless specifically stated otherwise includes primary,secondary and tertiary amines.

Unless otherwise stated, the term “carbamoyl” is used to include—NHC(O)OC₁—C₄alkyl, and —OC(O)NHC₁—C₄alkyl.

The term “halogen” includes fluorine, chlorine, bromine and iodineatoms.

The term “optionally substituted” is intended to include bothsubstituted and unsubstituted. Thus, for example, optionally substitutedaryl could represent a pentafluorophenyl or a phenyl ring. Further, thesubstitution can be made at any of the groups. For example, substitutedaryl(C₁₋₆)alkyl includes substitution on the aryl group as well assubstitution on the alkyl group.

The term “oxide” of heteroaryl groups is used in the ordinary well-knownchemical sense and include, for example, N-oxides of nitrogenheteroatoms.

Compounds described herein may contain one or more asymmetric centersand may thus give rise to diastereomers and optical isomers. The presentinvention includes all such possible diastereomers as well as theirracemic mixtures, their substantially pure resolved enantiomers, allpossible geometric isomers, and pharmaceutically acceptable saltsthereof. The above Formula I is shown without a definitivestereochemistry at certain positions. The present invention includes allstereoisomers of Formula I and pharmaceutically acceptable saltsthereof. Further, mixtures of stereoisomers as well as isolated specificstereoisomers are also included. During the course of the syntheticprocedures used to prepare such compounds, or in using racemization orepimerization procedures known to those skilled in the art, the productsof such procedures can be a mixture of stereoisomers.

The term “pharmaceutically acceptable salts” refers to salts preparedfrom pharmaceutically acceptable non-toxic bases or acids. When thecompound of the present invention is acidic, its corresponding salt canbe conveniently prepared from pharmaceutically acceptable non-toxicbases, including inorganic bases and organic bases. Salts derived fromsuch inorganic bases include aluminum, ammonium, calcium, copper (ic andous), ferric, ferrous, lithium, magnesium, manganese (ic and ous),potassium, sodium, zinc and the like salts. Particularly preferred arethe ammonium, calcium, magnesium, potassium and sodium salts. Saltsderived from pharmaceutically acceptable organic non-toxic bases includesalts of primary, secondary, and tertiary amines, as well as cyclicamines and substituted amines such as naturally occurring andsynthesized substituted amines. Other pharmaceutically acceptableorganic non-toxic bases from which salts can be formed include ionexchange resins such as, for example, arginine, betaine, caffeine,choline, N,N′-dibenzylethylenediamine, diethylamine,2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine,glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, tromethamine and the like.

When the compound of the present invention is basic, its correspondingsalt can be conveniently prepared from pharmaceutically acceptablenon-toxic acids, including inorganic and organic acids. Such acidsinclude, for example, acetic, benzenesulfonic, benzoic, camphorsulfonic,citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic,hydrochloric, isethionic, lactic, maleic, malic, mandelic,methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric,succinic, sulfuric, tartaric, p-toluenesulfonic acid and the like.Particularly preferred are citric, hydrobromic, hydrochloric, maleic,phosphoric, sulfuric, and tartaric acids.

The pharmaceutical compositions of the present invention comprise acompound represented by Formula I (or pharmaceutically acceptable saltsthereof) as an active ingredient, a pharmaceutically acceptable carrierand optionally other therapeutic ingredients or adjuvants. Thecompositions include compositions suitable for oral, rectal, topical,and parenteral (including subcutaneous, intramuscular, and intravenous)administration, although the most suitable route in any given case willdepend on the particular host, and nature and severity of the conditionsfor which the active ingredient is being administered. Thepharmaceutical compositions may be conveniently presented in unit dosageform and prepared by any of the methods well known in the art ofpharmacy.

In practice, the compounds represented by Formula I, or pharmaceuticallyacceptable salts thereof, of this invention can be combined as theactive ingredient in intimate admixture with a pharmaceutical carrieraccording to conventional pharmaceutical compounding techniques. Thecarrier may take a wide variety of forms depending on the form ofpreparation desired for administration, e.g., oral or parenteral(including intravenous). Thus, the pharmaceutical compositions of thepresent invention can be presented as discrete units suitable for oraladministration such as capsules, cachets or tablets each containing apredetermined amount of the active ingredient. Further, the compositionscan be presented as a powder, as granules, as a solution, as asuspension in an aqueous liquid, as a non-aqueous liquid, as anoil-in-water emulsion or as a water-in-oil liquid emulsion. In additionto the common dosage forms set out above, the compound represented byFormula I, or pharmaceutically acceptable salts thereof, may also beadministered by controlled release means and/or delivery devices. Thecompositions may be prepared by any of the methods of pharmacy. Ingeneral, such methods include a step of bringing into association theactive ingredient with the carrier that constitutes one or morenecessary ingredients. In general, the compositions are prepared byuniformly and intimately admixing the active ingredient with liquidcarriers or finely divided solid carriers or both. The product can thenbe conveniently shaped into the desired presentation.

Thus, the pharmaceutical compositions of this invention may include apharmaceutically acceptable carrier and a compound or a pharmaceuticallyacceptable salt of Formula I. The compounds of Formula I, orpharmaceutically acceptable salts thereof, can also be included inpharmaceutical compositions in combination with one or more othertherapeutically active compounds.

The pharmaceutical carrier employed can be, for example, a solid,liquid, or gas. Examples of solid carriers include lactose, terra alba,sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, andstearic acid. Examples of liquid carriers are sugar syrup, peanut oil,olive oil, and water. Examples of gaseous carriers include carbondioxide and nitrogen.

In preparing the compositions for oral dosage form, any convenientpharmaceutical media may be employed. For example, water, glycols, oils,alcohols, flavoring agents, preservatives, coloring agents and the likemay be used to form oral liquid preparations such as suspensions,elixirs and solutions; while carriers such as starches, sugars,microcrystalline cellulose, diluents, granulating agents, lubricants,binders, disintegrating agents, and the like may be used to form oralsolid preparations such as powders, capsules and tablets. Because oftheir ease of administration, tablets and capsules are the preferredoral dosage units whereby solid pharmaceutical carriers are employed.Optionally, tablets may be coated by standard aqueous or nonaqueoustechniques

A tablet containing the composition of this invention may be prepared bycompression or molding, optionally with one or more accessoryingredients or adjuvants. Compressed tablets may be prepared bycompressing, in a suitable machine, the active ingredient in afree-flowing form such as powder or granules, optionally mixed with abinder, lubricant, inert diluent, surface active or dispersing agent.Molded tablets may be made by molding in a suitable machine, a mixtureof the powdered compound moistened with an inert liquid diluent. Eachtablet preferably contains from about 1 mg to about 500 mg of the activeingredient and each cachet or capsule preferably containing from about 1to about 500 mg of the active ingredient.

Pharmaceutical compositions of the present invention suitable forparenteral administration may be prepared as solutions or suspensions ofthe active compounds in water. A suitable surfactant can be includedsuch as, for example, hydroxypropylcellulose. Dispersions can also beprepared in glycerol, liquid polyethylene glycols, and mixtures thereofin oils. Further, a preservative can be included to prevent thedetrimental growth of microorganisms.

Pharmaceutical compositions of the present invention suitable forinjectable use include sterile aqueous solutions or dispersions.Furthermore, the compositions can be in the form of sterile powders forthe extemporaneous preparation of such sterile injectable solutions ordispersions. In all cases, the final injectable form must be sterile andmust be effectively fluid for easy syringability. The pharmaceuticalcompositions must be stable under the conditions of manufacture andstorage; thus, preferably should be. preserved against the contaminatingaction of microorganisms such as bacteria and fungi. The carrier can bea solvent or dispersion medium containing, for example, water, ethanol,polyol (e.g. glycerol, propylene glycol and liquid polyethylene glycol),vegetable oils, and suitable mixtures thereof.

Pharmaceutical compositions of the present invention can be in a formsuitable for topical use such as, for example, an aerosol, cream,ointment, lotion, dusting powder, or the like. Further, the compositionscan be in a form suitable for use in transdermal devices. Theseformulations may be prepared, utilizing a compound represented byFormula I of this invention, or pharmaceutically acceptable saltsthereof, via conventional processing methods. As an example, a cream orointment is prepared by mixing hydrophilic material and water, togetherwith about 5 wt % to about 10 wt % of the compound, to produce a creamor ointment having a desired consistency.

Pharmaceutical compositions of this invention can be in a form suitablefor rectal administration wherein the carrier is a solid. It ispreferable that the mixture forms unit dose suppositories. Suitablecarriers include cocoa butter and other materials commonly used in theart. The suppositories may be conveniently formed by first admixing thecomposition with the softened or melted carrier(s) followed by chillingand shaping in moulds.

In addition to the aforementioned carrier ingredients, thepharmaceutical formulations described above may include, as appropriate,one or more additional carrier ingredients such as diluents, buffers,flavoring agents, binders, surface-active agents, thickeners,lubricants, preservatives (including anti-oxidants) and the like.Furthermore, other adjuvants can be included to render the formulationisotonic with the blood of the intended recipient. Compositionscontaining a compound described by Formula I, or pharmaceuticallyacceptable salts thereof, may also be prepared in powder or liquidconcentrate form.

Experimental Protocols

-   -   Assessing the Activity of Selected Compounds to Inhibit NR1A/2B        NMDA Receptor Activation (FLIPR Assay)

The activity of selected compounds to inhibit NR1A/2B NMDA receptoractivation measured as NR1A/2B receptor-mediated Ca²⁺ influx is assessedby the following procedure:

NR1A/2B receptor transfected L(tk) cells are plated in 96-well format at3×10⁶ cells per plate and grown for one—two days in normal growth media(Dulbeccos MEM with Na pyruvate, 4500 mg glucose, pen/strep, glutamine,10% FCS and 0.5 mg/mL geneticin). NR1A/2B-expression in these cells isinduced by the addition of 4 nM dexamethasone in the presence of 500 μMketamine for 16–24 hours. After receptor induction cells are washedusing a Labsystem Cellwasher two times with assay buffer (Hanks balancedsalt solution (HBSS-Mg⁺⁺ free) containing 20 mM HEPES, 0.1% BSA, 2 mMCaCl₂ and 250 μM probenecid). The cells of each 96 well cell plate areloaded with the Ca⁺⁺ sensitive dye Fluo-3 (Molecular Probes, Inc.) at 4μM in assay buffer containing 0.5% FBS, and 0.04% pluronic F-127(Molecular Probes, Inc.) for 1 h at 37° C. avoiding light. The cells arethen washed with the Cellwasher four times with assay buffer leavingthem in 100 μL buffer. Test compounds in solution are pipetted by FLIPR(Fluorometric Imaging Plate Reader) into each test well for a 2 minpretreatment. During this time the fluorescence intensity is recorded(excitation at 488 nm and emission at 530 nm). The glutamate/glycine 50μL agonist solution (final concentration 1 μM/1 μM) is then added byFLIPR into each well already containing 150 μL of buffer (containing thetest compound or vehicle) and the fluorescence is continuously monitoredfor 10 min. The endpoint fluorescence values are used to determine anIC₅₀ value comparing the agonist-stimulated signal for the vehicle alonesample and that for the cells incubated with each concentration of testcompound.

-   -   Determining the Apparent Dissociation Constant (Ki) of Compounds        for Human NR1A/NR2B Receptors (Binding Assay)

The radioligand binding assay is performed at room temperature in96-well microtiter plates with a final assay volume of 1.0 mL in 20 mMHEPES buffer (pH 7.4) containing 150 mM NaCl. Solutions of testcompounds were prepared in DMSO and serially diluted with DMSO to yield20 μL of each of 10 solutions differing by 3-fold in concentration.Non-specific binding (NSB) using hot AMD-1 (10 μM final concentration)and total binding (TB) by using DMSO (2% final concentration). Asolution of NR1A/NR2B receptors (40 pM final concentration) andtritiated AMD-2 (1 nM final concentration) were added to the testcompounds. After 3 h of incubation at room temperature, samples arefiltered through Packard GF/B filters (presoaked in 0.05% PEI,polyethyleninine Sigma P-3143) and washed 10 times with 1 mL of cold 20mM HEPES buffer per wash. After vacuum drying of the filter plates, 40μL of Packard Microscint-20 was added and bound radioactivity determinedin a Packard TopCount. The apparent dissociation constant (Ki), themaximum percentage inhibition (% I_(max)), the minimum percentageinhibition (% I_(min)) and the hill slope (nH) were determined by anon-linear least squares fitting the bound CPM data to Equation #1below.

$\begin{matrix}{{{CPM}\mspace{14mu}{Bound}} = {\frac{({SB})( {{\% I_{\max}} - {\% I_{\min}}} )}{( {1 + ( {\lbrack{Drug}\rbrack/( {{{Ki}\lbrack {{AMD} - 2} \rbrack}/K_{D}} )} )^{nH}} )} + {NSB} + {({SB})( {1 - {\% I_{\max}}} )}}} & \text{Equation~~~\#1}\end{matrix}$

-   -   where, K_(D) is the apparent dissociation constant for the        radioligand for the receptor as determined by hot saturation and        SB is the specifically bound CPM determined from the difference        of TB and NSB.

Compounds AMD-1 and AMD-2 can be synthesized in accordance with thefollowing general reaction schemes.

In accordance with scheme 1, hydrogen chloride is bubbled through asolution of the appropriately substituted benzonitrile 1 in methanol atroom temperature. The volatiles are removed under reduced pressure andthe resulting residue is triturated with ether and filtered to yield thedesired imidate 2. Imidate 2 is dissolved in methanol at ambienttemperature, treated with amine 3 at ambient temperature and stirredunder argon. The volatiles are removed under reduced pressure and theresidue purified by preparative HPLC or trituration with ether to affordamidine Ia.

In accordance with scheme 2, at room temperature under argon, amine 3ais dissolved in ether and was treated with 1-M hydrogen chloride inether (1 equiv.) in a single portion. The resulting precipitate isstirred vigorously for 10 minutes. The volatiles are removed underreduced pressure. The residue is suspended in toluene, cooled to 0° C.under argon, treated with 2.0-M trimethylaluminum (1.05 equiv.) in adropwise manner, and stirred for 45 minutes at room temperature toafford intermediate 6 (not isolated). Compound 6 is added to a solutionof nitrile 1 in toluene. The reaction is heated to 80° C. withoutstirring in a sealed tube for 18 h, cooled to ambient temperature,poured onto a silica gel column and eluted with methanol/dichloromethaneto give the amidine 4.

Preparation of [¹²⁵I]AMD-1

Tritiated AMD-1 was prepared by the following procedure: A mixture ofAMD-1, hydrochloride salt, (5 mg, 0.012 mmol) in dioxane (0.2 mL)containing triethylamine (4 μL) was treated with hexamethylditin (5 μL),a catalytic amount of palladium catalyst and heated at 100° C. for 45minutes. The reaction was cooled to room temperature, filtered through aglass wool plug, rinsed with methanol and concentrated in vacuo to give10.7 mg of a brown oil. The oil was dissolved in methylene chloride andpassed through a small silica column eluting with methylene chloridefollowed by 5% methanol/methylene chloride. Fractions containing thetrimethylstannane (Rf 0.26 in 10% methanol/methylene chloride) werepooled and concentrated in vacuo to give the trimethylstannane as aclear colorless oil. This material was further purified by HPLC (C18Econosil, 10×250 mm, 20 minute linear gradient, 30% MeCN:70% H₂O (0.1%TFA) to 90% MeCN, 3 mL/min, 254 nm, retention time 15 minutes) to givethe trimethylstannane.

A Na¹²⁵I shipping vial (10 mCi, Amersham) was charged with a stir bar,an iodobead, 50 μL of methanol and stirred five minutes at roomtemperature. A solution of the trimethylstannane (0.1 mg) in 50 μL ofmethanol containing 5 μL of trifluoroacetic acid was added and thereaction was stirred for five minutes. The reaction was quenched with 50μL of ammonium hydroxide and purified by HPLC (C18 Vydac protein andpeptide column, 4.6×250 mm, 20 minute linear gradient, 30% MeCN:70% H₂O(0.1% TFA) to 90% MeCN, 1 mL/min, retention time 11 minutes). Fractionscontaining the radioactive product were pooled and concentrated in vacuoto give 989 μCi of [¹²⁵I]AMD-1 with a specific activity of 898 Ci/mmolas measured by UV absorbance at 272 nm.

Synthesis of Tritiated AMD-2

Tritiated AMD-2 was prepared by the following procedure: The phenol ofAMD-2 (2 mg, 0.008 mmol) dissolved in dimethylformamide (0.6 mL) andpotassium carbonate (1.2 mg) for 1 h. High specific activity tritiatedmethyl iodide (50 mCi, 0.0006 mmol, in toluene 1 mL, AmericanRadiolabeled Chemicals) was added at room temperature and stirred for 2hours. The reaction mixture was filtered using a Whatman PTFE 0.45 μmsyringeless filter device to remove any insoluble potassium carbonate,washed with Abs. ethanol (2 mL, Pharmco), and the combined filtrateswere concentrated to dryness at room temperature using a rotaryevaporator; this also removed any unreacted tritiated methyl iodide. Theresidue was purified by HPLC chromatography on a Phenomenx Luna C8semi-prep column (Luna 5 micro C8(2), 250×10.0 mm) using a gradientsystem of 20/80 acetonitrile/water with 0.1% trifluoroacetic acid to100% acetonitrile with 0.1% trifluoroacetic acid in 20 min. Totalactivity of the product was 8 mCi. Further purification was effected byabsorption onto a Waters C-18 Sep-Pak column (Waters Sep-Pak PLUS C18)and elution with water followed by absolute ethanol. The product wasdiluted with absolute ethanol (10 mL) before submission for finalanalysis.

The compounds of this invention exhibit IC₅₀'s of less than 50 μM in theFLIPR and binding assays. Thus, the compounds and pharmaceuticalcompositions of this invention have been found to exhibit biologicalactivity as NMDA NR2B antagonists. Advantageously, the IC₅₀'s should beless than 1 μM in the FLIPR and binding assays. Even moreadvantageously, the IC₅₀'s should be less than 0.1 μM in the FLIPR andbinding assays. Accordingly, another aspect of the invention is thetreatment of pain, migraine, depression, anxiety, schizophrenia,Parkinson's disease, or stroke—maladies that are amenable toamelioration through inhibition of NMDA NR2B receptors—by theadministration of an effective amount of the compounds of thisinvention. Further, another aspect of the invention is the treatment ofglaucoma and tinitis—maladies that are also amenable to ameliorationthrough inhibition of NMDA NR2B receptors—by the administration of aneffective amount of the compounds of this invention.

The abbreviations used herein are as follows unless specified otherwise:

BH₃*THF Tetrahydrofuran/borane complex BOC t-Butoxycarbonyl BOC₂Ot-Butoxycarbonyl anhydride CBZ Carbobenyloxy CBZ-Cl Carbobenzyl chlorideDCM Dichloromethane DIPEA Diisopropylethylamine DMFN,N-Dimethylformamide DMF-DMA Dimethylformamide-Dimethylacetal DMSODimethylsulfoxide EDC 3-Ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride h hours HOAt 1-Hydroxy-7-azabenzotriazole IPA IsopropanolmCPBA meta Chloroperbenzoic acid min minutes NMR nuclear magneticresonance r.t. or rt room temperature sat. saturated TEA TriethylamineTFA Trifluoroacetic acid THF Tetrahydrofuran

The following examples are provided to more fully illustrate the presentinvention, and are not to be construed as limiting the scope of theclaims in any manner.

EXAMPLES

The compounds of this invention can be prepared by procedures shownbelow.

Intermediates:

Intermediate 1a:

Carbonic acid 2,5-dioxo-pyrrolidin-1-yl ester 4-methyl-benzyl ester

Disuccinimidyl carbonate (5.03 g, 19.65 mmol) in 30 mL MeCN and 30 mLDCM was treated with 4-methylbenzyl alcohol (2.4 g, 19.6 mmol) followedby DMAP (1.20 g, 9.82 mmol). The resulting cloudy reaction mixture wasstirred overnight at rt, poured into 100 mL water, and partitioned. Theorganic layer was dried over anhydrous sodium sulfate and the solventevaporated. The solid thus obtained was stirred with approx. 25 mLether, filtered, and the resulting product was washed with a smallvolume of ether and dried.

Ref: Chem. Pharm. Bull., 38(1):110–115(1990).

The following compounds were similarly prepared in the manner describedabove for INTERMEDIATE 1a:

Intermediate 1b:

Carbonic acid 2,5-dioxo-pyrrolidin-1-yl ester 4-chloro-benzyl ester

Intermediate 1c:

Carbonic acid 2,5-dioxo-pyrrolidin-1-yl ester 4-fluoro-benzyl ester

Intermediate 1d:

Carbonic acid 2,5-dioxo-pyrrolidin-1-yl ester 4-ethyl-benzyl ester

Intermediate 1e:

Carbonic acid 2,5-dioxo-pyrrolidin-1-yl ester 4-isopropyl-benzyl ester

Utilizing the carbonic acid derivatives described above as Intermediates1a–1e, and following the procedure described below in EXAMPLE 15, step1, the following INTERMEDIATES 2a–2e were obtained:

Intermediate 2a:

4-Methylbenzyl 4-(aminomethyl)piperidine-1-carboxylate

Intermediate 2b:

4-Chlorobenzyl 4-(aminomethyl)piperidine-1-carboxylate

Intermediate 2c:

4-Fluorobenzyl 4-(aminomethyl)piperidine-1-carboxylate

Intermediate 2d:

4-Ethylbenzyl 4-(aminomethyl)piperidine-1-carboxylate

Intermediate 2e:

4-Isopropylbenzyl 4-(aminomethyl)piperidine-1-carboxylate

The carboxylic acids used in the coupling steps were either commerciallyavailable or prepared according to the following references:

Structure Name Reference

6-Hydroxy-pyridazine-3-carboxylic acid M. Morishita,Chem. Pharm.Bull.,42: 371(1994).

4-Methanesulfonylamino-benzoic acid L. Exner, Collect CzechChem. Comm,35: 1371–1374(1970).

4-Hydroxy-3-iodo-benzoicacid L. C. King, et al., J. Amer.Chem. Soc., 67:2089(1945).

3-Fluoro-4-hydroxy-benzoic acid J. Minor et al., J. Org.Chem., (1952),17, 1425.

2-Fluoro-4-hydroxy-benzoic acid G. Gray et al., Mol. Cryst.Liq. Cryst.,67: 1–24(1981).

Thiazole-4-carboxylic acid H. Erlenmeyer et al., Helv.Chim. Acta., 28:362(1945).

2H-Pyrazole-3-carboxylicacid Sokolov et al., J. Gen.Chem. USSR (Eng.)52:2291(1982).

5-Oxo-4,5-dihydro-1H-[1,2,4]triazole-3-carboxylicacid GehlenAnn (1952)577, 237–241.

Thiazole-5-carboxylic acid H. Erlenmeyer et al., Helv.Chim. Acta.,30:1865(1947).

2-Bromo-isonicotinic acid A. Campbell et al.,Austral. J. Chem.,24:377(1971).

5-Methyl-3H-imidazole-4-carboxylic acid G. Wellman et al.,Synthesis356(1984).

2-Methyl-1H-pyrrole-3-carboxylic acid E. Benary, ChemischeBerichte, 44:493(1911).

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3-methyl-3H-imidazole-4-carboxylic acid EP 0306868

Example 1 4-[(4-Hydroxy-benzoylamino)-methyl]-piperidine-1-carboxylicacid benzyl ester

Step 1:

Preparation of Benzyl 4-(aminomethyl)piperidine-1-carboxylate

4-Aminomethylpiperidine (40 g, 350 mmol) and benzaldehyde (37.3 mL, 368mmol) in toluene (600 mL) were heated to reflux under dean starkconditions for 2 h. The resulting reaction mixture was cooled to roomtemperature and 500 mL dichloromethane was added. The resulting solutionwas cooled to 5° C. and treated with N-(benzyloxycarbonyloxy)succinimide(91.7 g, 368 mmol). After 10 min, the cooling bath was removed and thereaction mixture stirred for 1 h. The solvents were evaporated and theresulting residue was stirred with 400 mL THF and 400 mL 2 M HCl for 1h. The mixture was concentrated to remove organics and was thenextracted with ether (3×300 mL). The aqueous phase was adjusted to pH14with 50% NaOH and extracted with ethyl acetate. The organic layer waswashed with water and brine, dried over anhydrous sodium sulfate, andthe solvent evaporated to give benzyl4-(aminomethyl)piperidine-1-carboxylate as an oil.

¹HNMR 500 MHz (δ, CDCl₃) δ: 7.4–7.2 (m, 5H); 5.12 (s, 2H); 4.20 (brs,2H); 2.77 (brs, 2H); 2.58 (d, J=6.6 Hz, 2H) 1.9–1.7 (m, 2H); 1.0–1.5 (m,5H).

Step 2:

Preparation of4-[(4-Hydroxy-benzoylamino)-methyl]-piperidine-1-carboxylic acid benzylester

To a mixture of 4-hydroxybenzoic acid (2.5 g, 0.0182 mol),1-hydroxybenzotriazole hydrate (3.33 g, 0.0218 mol), benzyl4-(aminomethyl)piperidine-1-carboxylate (4.5 g, 0.0182 mol) andtriethylamine (3.03 mL, 0.0218 mol) in DMF (30mL) was added1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (4.2 g,0.0218 mol) and the mixture allowed to stir at rt for 18 h. The mixturewas quenched into water (200 mL) and extracted with ethyl acetate (200nL). The ethyl acetate extract was washed with 10% aqueous sodiumbicarbonate (100 mL), brine (50 mL), dried over sodium sulfate, andfiltered. The filtrate was concentrated in vacuo and the residuechromatographed on silica using 10–20% acetone/dichloromethane to give6.3 g of 4-[(4-hydroxy-benzoylamino)-methyl]-piperidine-1-carboxylicacid benzyl ester as a foam. The foam was dissolved in hot isopropylacetate (125 mL), filtered, and allowed to cool and crystallize. Thereaction volume was reduced in vacuo to 50 mL, allowed to stir overnightat rt and filtered. The resulting solid was dried in vacuo (50° C.)yielding the 4-[(4-hydroxy-benzoylamino)-methyl]-piperidine-1-carboxylicacid benzyl ester.

M.P. 122–123° C. M.S(M+1): 369.

¹H NMR 300 MHz (δ, CDCl₃) δ: 7.64 (d, 2H); 7.4–7.2 (m, 5H); 6.86 (d,2H); 6.18 (m, 1H); 5.85 (s, 1H1); 5.15 (s, 2H); 4.20 (brs, 2H); 3.35(brs, 2H); 2.77 (brs, 2H); 1.9–1.7 (m, 3H); 1.3–1.1 (m, 2H).

Analysis Calcd. for C₂₁H₂₄N₂O4: C, 68.46; H, 6.57; N, 7.60;

Found: C, 68.23; H, 6.61; N, 7.48.

The following compounds were prepared in a manner similar to that usedabove for the preparation of4-[(4-hydroxy-benzoylamino)-methyl]-piperidine-1-carboxylic acid benzylester, using the appropriate acid in place of the 4-hydroxybenzoic acid.References or experimental procedures are shown for the preparation ofnon-commercially available acids. Appropriately substituted benzyl4-(aminomethyl)piperidine-1-carboxylates were prepared in a similarmanner to that described above in EXAMPLE 1, step 1, with the necessaryN-(benzyloxycarbonyloxy)succinimides prepared as previously described(Chem. Pharm Bull 1990, 38(1) 110–115).

EX. Name Structure Data 2.4-{[(Pyrazine-2-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacidbenzyl ester

M.S(M+1): 370 ¹HNMR 300 MHz(δ,CDCl₃) δ: 12.10(brs,1H); 8.02(d, 1H,J=2.5Hz); 7.77(dd,1H, J=7.7 and2.5 Hz); 7.4–7.2(m,5H); 6.59(d, 2H,J=7.7 Hz);6.12(m,1H); 5.12(s, 2H);4.20(brs, 2H);3.30(brs, 2H); 2.77(brs,2H);2.0–1.8(m, 3H);1.3–1.1(m, 2H). 3.4-{[(3-Amino-pyridine-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacidbenzyl ester

M.S(M+1): 369NMR(300 MHz,CDCl₃) δ: all broad 4.4-{[(6-Hydroxy-pyridazine-3-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacidbenzyl ester

M.S(M+1): 371NMR(300 MHz,CDCl₃) δ: 11.55(brs,1H); 8.04(d, 1H,J=9.8Hz);7.4–7.1(m, 5H);7.04(d, 1H, 9.8 Hz);5.12(s, 2H); 4.22(brs,2H);3.30(brs, 2H); 2.80(m,2H); 1.8–1.6(m, 3H);1.3–1.1(m, 2H) 5.4-[(4-Methanesulfonylamino-benzoylamino)-methyl]-piperidine-1-carboxylicacidbenzyl ester

M.S(M+1): 446 NMR(300 MHz, CDCl₃))δ: 7.75(d, 2H,J=8.6 Hz); 7.4–7.2(m,5H);7.25(d, 2H, J=8.6 Hz);6.95(brs, 1H);6.25(brs, 1H);5.12(s, 2H);4.21(brs,2H); 4.36(brs, 2H);3.05(s, 3H);2.78(brs, 2H); 1.9–1.6(m,3H);1.3–1.1(m, 2H). 6.4-[(2,4-Dihydroxy-benzoylamino)-methyl]-piperidine-1-carboxylicacidbenzyl ester

M.S(M+1): 385 NMR(300 MHz, CDCl₃))δ: 12.55(s, 1H); 7.5–7.3(m, 5H);7.22(d,1H, J=8.6 Hz);6.41(d, 1H, J=2.5 Hz);6.34(dd, 1H, J=8.6and 2.5Hz); 6.22(m,1H); 5.13(s, 2H);4.22(brs, 2H);3.33(brs, 2H); 2.79(brs,2H);1.8–1.6(m, 3H);1.3–1.0(m, 2H). 7.4-[(3,4-Dihydroxy-benzoylamino)-methyl]-piperidine-1-carboxylicacidbenzyl ester

M.S(M+1): 385 NMR(300 MHz, CDCl₃))δ: 7.57(d, 1H,J=1.6 Hz); 7.5–7.3(m,5H);7.10(dd, 1H, J=8.2and 1.6Hz); 6.86(d,1H, J=8.2 Hz);6.30(m, 1H);5.12(s, 2H);4.18(brs, 2H);3.32(brs, 2H); 2.76(brs,2H); 1.8–1.4(m,3H);1.3–1.0(m, 2H). 8.4-[(4-Hydroxy-3-iodo-benzoylamino)-methyl]-piperidine-1-carboxylicacidbenzyl ester

M.S(M+1): 495NMR(300 MHz,CDCl₃)) δ: 8.11(d,1H, J=2.1 Hz);7.63(dd, 1H,J=8.4and 2.1 Hz); 7.5–7.3(m, 5H); 7.00(d,1H, J=8.4 Hz);6.10(m, 1H);5.12(s, 2H);4.21(brs, 2H);3.33(brs, 2H); 2.78(brs,2H); 1.8–1.6(m,3H);1.3–1.0(m, 2H). 9.4-[(3-Fluoro-4-hydroxy-benzoylamino)-methyl]-piperidine-1-carboxylicacidbenzyl ester

M.S(M+1): 387NMR(300 MHz,CDCl₃)) δ: 7.56(dd,1H, J=11.0 and1.9 Hz);7.5–7.3(m, 6H);7.03(t, 1H, J=8.4 Hz);6.16(m, 1H); 5.12(s,2H); 4.20(brs,2H);3.33(brs, 2H);2.78(brs, 2H);1.9–1.6(m, 3H); 1.3–1.0(m, 2H). 10.4-[(2-Fluoro-4-hydroxy-benzoylamino)-methyl]-piperidine-1-carboxylicacidbenzyl ester

M.S(M+1): 387NMR (300 MHz,CDCl₃)) δ: 7.94(t,1H, J=9.0 Hz); 7.5–7.2(m,5H); 6.78(m,1H); 7.73(dd, 1H,J=8.7 and 2.4 Hz);6.61(dd, 1H, J=13.8and2.2 Hz); 5.13(s,2H); 4.20(brs, 2H);3.37(brs, 2H);2.78(brs, 2H);1.9–1.6(m,3H); 1.3–1.0(m, 2H). 11.4-{[(1H-Benzoimidazole-5-carbonyl)-amino]-methyl}-piperidin-1-carboxylicacidbenzyl ester

MS Exact mass:393.1940.Experimental forC₂₁H₂₄N₄O₃:393.1921. ¹H NMR(400MHz, δ, CDCl₃):8.13–8.11(m, 2H),7.67(brs, 2H), 7.35–7.28(m, 5H),6.52(d,J=5.98 Hz, 2H),5.13(s, 2H),4.21(brs, 2H), 3.39(brs,2H), 2.79(brs,2H),1.90–1.78(m, 1H),1.78–1.62(m, 2H),1.29–1.16(m, 2H). 12.4-{[(1H-Benzotriazole-5-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacidbenzyl ester

MS Exact mass:394.1896.Experimental forC₂₁H₂₃N₅O₃:394.1874. ¹H NMR(400MHz, δ, CDCl₃):8.37(s, 1H), 7.78(d,J=8.68 Hz, 2H), 7.66–7.64(m, 2H),7.31–7.22(m, 5H),6.65(vbs, 2H), 5.09(s,2H), 4.13(brd,J=11.06,2H),3.35(brs, 2H), 2.71(brs,2H), 1.90–1.77(m,1H), 1.71(brd,J=11.61Hz,2H),1.26–1.12(m, 2H). 13.4-[(4-Cyano-benzoylamino)-methyl]-piperidine-1-carboxylic acidbenzylester

¹H NMR(δ, CDCl₃):7.86(d, J=8.05 Hz,2H), 7.74(d,J=8.05 Hz, 2H),7.25–7.4(m, 5H), 6.31(brt,J=5.61 Hz, 1H),5.12(s, 2H), 4.22(brs,2H),3.37(brs, 2H),2.79(brs, 2H), 1.7–1.9(m, 3H), 1.23(m, 2H). 14.4-{[(6-Hydroxy-pyridine-3-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacid 4-methyl-benzyl ester

M.S(M+1): 384NMR(300 MHz,CDCl₃) δ: 12.20(brs,1H); 8.02(d, 1H,J=2.5 Hz);7.75(dd,1H, J=9.6 and2.5 Hz); 7.24(d, 2H,J=7.9 Hz); 7.15(d, 2H,J=7.9Hz); 6.56(d,1H, J=9.6 Hz);6.20(m, 1H); 5.07(s, 2H);4.20(brs,2H);3.30(brs, 2H); 2.35(brs,2H); 1.8–1.6(m, 3H);1.3–1.1(m, 2H). 15.4-{[(6-Hydroxy-pyridazine-3-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacid 4-methyl-benzyl ester

M.S(M+1): 385NMR(300 MHz,CDCl₃)) δ: 11.9(s,1H); 8.05(d, 1H,J=9.9 Hz);7.25(d,2H, J=7.9 Hz);7.16(d, 2H, J=7.9 Hz);7.04(d, 1H, J=9.9 Hz);5.08(s,2H);4.20(brs, 2H);3.32(brs, 2H); 2.76(m,2H); 2.35(s, 3H); 1.8–1.6(m,3H); 1.3–1.1(m, 2H). 16.4-{[(6-Hydroxy-pyridine-3-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacid 4-fluoro-benzyl ester

M.S(M+1): 388NMR(300 MHz,CDCl₃)) δ: 12.2(s,1H); 8.03(d, 1H,J=2.6 Hz);7.77(dd,1H, J=9.6 and2.6 Hz); 7.34(m, 2H);7.03(t, 2H, J=8.6 Hz);6.57(d,1H,J=9.6 Hz); 5.07(s,2H); 4.20(brs, 2H);3.31(brs, 2H);2.76(brs, 2H);2.35(s,3H); 1.8–1.6(m, 3H);1.3–1.1(m, 2H). 17.4-{[(6-Hydroxy-pyridine-3-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacid 4-chloro-benzyl ester

M.S(M+1): 404NMR(300 MHz,CDCl₃)) δ: 11.8(brs,1H); 8.02(d, 1H,J=2.4 Hz);7.74(dd,1H, J=9.6 and2.4 Hz); 7.4–7.2(m, 4H);6.58(d, 1H, J=9.6Hz);6.03(m, 1H);5.08(s, 2H);4.20(brs, 2H); 3.31(brs,2H); 2.78(brs,2H);1.8–1.4(m, 3H); 1.3–1.1(m, 2H). 18.4-{[(6-Hydroxy-pyridine-3-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacidindan-2-yl ester

M.S(M+1): 396NMR(300 MHz,CDCl₃)) δ: 12.0(brs,1H); 8.01(d, 1H,J=2.5 Hz);7.74(dd,1H, J=9.6 and2.5 Hz); 7.3–7.1(m, 4H);6.57(d, 1H, J=9.6Hz);6.04(m, 1H); 5.46(m, 1H);4.3–4.1(m, 2H); 3.32(m,4H); 3.04(d,1H,J=3.2 Hz); 3.00(d,1H, J=3.2Hz);2.72(m, 2H); 1.8–1.6(m,3H);1.3–1.0(m,2H). 19.4-[(4-Hydroxy-benzoylamino)-methyl]-piperidine-1-carboxylic acid4-fluoro-benzyl ester

M.S(M+1): 387 NMR(300 MHz, CDCl₃))δ: 7.65(d, 2H, J=8.6 Hz);7.33(m,2H);7.03(t, 2H, J=8.6 Hz);6.86(d, 2H,J=8.6 Hz); 6.64(s,1H); 6.22(m,1H);5.08(s, 2H); 4.14(brs,2H); 3.33(brs, 2H);2.67(brs, 2H); 1.8–1.6(m,3H);1.3–1.0(m, 2H). 20.4-[(4-Hydroxy-benzoylamino)-methyl]-piperidine-1-carboxylic acid4-chloro-benzyl ester

M.S(M+1): 403NMR(300 MHz,CDCl₃)) δ: 7.66(d,2H, J=8.6 Hz);7.30(m, 4H);6.86(d, 2H,J=8.6 Hz); 6.33(s,1H); 6.22(m, 1H);5.08(s, 2H); 4.14(brs,2H);3.33(brs, 2H);2.77(brs, 2H); 1.8–1.6(m, 3H);1.3–1.0(m, 2H). 21.4-[(4-Hydroxy-benzoylamino)-methyl]-piperidine-1-carboxylicacidindan-2-yl ester

M.S(M+1): 395 NMR(300 MHz, CDCl₃))δ: 7.63(d, 2H, J=8.6 Hz);7.3–7.1(m,4H);6.85(d, 2H, J=8.6 Hz);6.27(m, 1H);5.46(m, 1H); 4.3–3.8(m, 2H);3.3(dd, 4H,J=16.9 and 6.6 Hz);3.0(dd, 2H, J=7.0and 3.2 Hz); 2.69(dt,2H,J=13.2 and2.7 Hz); 1.8–1.6(m, 3H);1.3–1.0(m, 2H). 22.4-[(4-Hydroxy-benzoylamino)-methyl]-piperidine-1-carboxylic acid4-methyl-benzyl ester

M.S(M+1): 383NMR(300 MHz,CDCl₃)) δ: 7.64(d,2H, J=8.8 Hz);7.24(d, 1H,J=8.0 Hz);7.15(d, 1H, J=8.0 Hz);6.86(d, 2H,J=8.8 Hz); 6.24(m,1H);5.08(s, 2H);4.18(brs, 2H);3.32(brs, 2H); 2.75(brs,2H); 2.34(s,3H);1.8–1.6(m, 3H); 1.3–1.0(m, 2H). 23.4-{[(Pyridine-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylic acid4-methyl-benzyl ester

¹H NMR(δ, CDCl₃):8.75(d, J=5.86Hz,2H), 7.60(d, J=4.89 Hz,2H),7.25(d,J=8.05 Hz, 2H),7.16(d, J=8.05 Hz, 2H),6.32(brt, 1H),5.08(s, 2H),4.22(brs,2H), 3.37(brs, 2H),2.77(brs, 2H),2.35(s, 3H), 1.7–1.9(m,3H),1.21(m, 2H). 24.4-{[(Pyridine-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylic acid4-chloro-benzyl ester

¹H NMR (δ, CDCl₃):8.75(d, J=4.64 Hz,2H), 7.60(d, J=5.13 Hz,2H),7.32(d,J=8.05 Hz, 2H),7.28(d, J=8.55 Hz, 2H),6.35(brt, 1H),5.08(s, 2H),4.22(brd,2H), 3.37(brd, 2H),2.79(brs, 2H), 1.7–1.9(m, 3H), 1.23(m, 2H).25. 4-{[(Pyridine-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacid 4-fluoro-benzyl ester

¹H NMR (δ, CDCl₃):8.75(d, J=5.61 Hz,2H), 7.60(d, J=6.11 Hz,2H),7.28(dd,J=5.62, 8.3 Hz, 2H),7.04(t, J=8.8 Hz,2H), 6.33(brt, 1H),5.08(s,2H),4.23(brd, 2H), 3.38(brd,2H), 2.78(brs, 2H),1.7–1.9(m, 3H),1.22(m,2H). 26.4-[(4-Hydroxy-3-methyl-benzoylamino)-methyl]-piperidine-1-carboxylicacidbenzyl ester

¹H NMR (δ, CDCl₃):7.56(brs, 1H),7.49(dd, J=2.2, 8.3 Hz,1H),7.25–7.4(m,5H), 6.79(d, J=8.3 Hz,1H), 6.13(brt, 1H),5.55(s, 1H),5.12(s,2H), 4.22(brs,2H), 3.33(brs, 2H),2.78(brs, 2H),2.28(s, 3H),1.7–1.9(m,3H), 1.23(m, 2H). 27.4-[(3-Chloro-4-hydroxy-benzoylamino)-methyl]-piperidine-1-carboxylicacidbenzyl ester

¹H NMR (δ, CDCl₃):7.80(d, J=2.2 Hz,1H), 7.57(dd, J=2.2,8.55 Hz, 1H),7.25–7.4(m, 5H), 7.05(d,J=8.55 Hz, 1H),6.13(brt, 1H), 6.04(brs,1H),5.12(s, 2H),4.22(brs, 2H), 3.33(brs,2H), 2.78(brs, 2H),1.7–1.9(m,3H),1.23(m, 2H). 28.4-{[(Thiophene-3-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacidbenzyl ester

¹H NMR (δ, CDCl₃):7.84(s, 1H), 7.41–7.27(m, 7H), 6.24(brt,1H), 5.06(s,2H),4.19(brd, 2H),3.30(brs, 2H), 2.77(brt,2H), 1.9–1.7(m,3H), 1.18(m,2H). 29.4-{[(Thiazole-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacidbenzyl ester

¹H NMR (δ, CDCl₃):8.74(d, 1H), 8.17(d,1H), 7.50(brt, 1H),7.26(m, 5H),5.11(s,2H), 4.19(brs, 2H),3.35(brs, 2H), 2.78(brt,2H), 1.9–1.7(m,3H),1.21(m, 2H). 30.4-{[(2H-Pyrazole-3-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacidbenzyl ester

¹H NMR (δ, CDCl₃):7.59(d, J=1.3 Hz,1H), 7.36–7.28(m,5H), 7.07(brt,1H),6.82(d, J=1.3 Hz,1H), 5.13(s, 2H),4.20(brs, 2H),3.37(brs, 2H),2.78(brt,2H), 1.9–1.7(m, 3H),1.21(m, 2H). 31.4-{[(5-Oxo-4,5-dihydro-1H-[1,2,4]triazole-3-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacidbenzyl ester

¹H NMR (500 MHz,δ, CDCl₃): 11.55(s,br, 2H), 7.45–7.30(m,6H), 5.12(s,2H),4.19(s, 2H), 3.25(m,2H), 2.75(m, 2H),1.85–1.65(m, 3H),1.15(m, 2H).32.4-{[(2H-[1,2,4]Triazole-3-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacidbenzyl ester

¹H NMR (500 MHz,δ, DMSO-d₆):14.60(s, br, 1H), 8.80–8.30(s,br, 2H),7.40–7.30(m,5H), 5.07(s, 2H),3.98(d, 2H), 3.15(t,2H), 2.77(m, br,2H),1.77(m, 1H), 1.63(d,2H), 1.05(m, 2H). 33.4-{[(Thiazole-5-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacidbenzyl ester

¹H NMR (500 MHz,δ, DMSO-d₆):9.21(s, 1H), 8.74(m, 1H),8.46(s, 1H),7.40–7.28(m, 5H), 5.09(s,2H), 4.00(d, 2H),3.12(t, 2H), 2.90–2.70(m, br,2H),1.80–1.65(m, 3H),1.05(m, 2H). 34.4-{[(1H-Pyrazole-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacidbenzyl ester

¹H NMR (500 MHz,δ, CD₃OD): 8.2–7.8(s, br, 2H), 7.36–7.25(m, 5H), 5.11(s,2H),4.15(m, 2H), 3.23(m,2H), 2.90–2.75(s,br, 2H), 1.90–1.70(m,3H),1.20–1.10(m, 2H). 35.4-{[(2-Bromo-pyridine-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacidbenzyl ester

¹H NMR (500 MHz,δ, DMSO-d₆):8.88(m, 1H), 8.54(d, 1H),7.99(s, 1H),7.78(d,1H), 7.38–7.28(m,5H), 5.07(s, 1H),4.00(d, 2H), 3.16(t,2H),2.90–2.70(m,2H), 1.80–1.65(m,3H), 1.09(m, 2H). 36.4-{[(1H-Pyrrole-2-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacidbenzyl ester

¹H NNR (δ, CDCl₃):9.55(brs, 1H), 7.39–7.28(m, 5H), 6.92(m,1H), 6.57(m,1H),6.22(m, 1H), 6.01(brt,1H), 5.08(s, 2H),4.20(brs, 2H), 3.28(brs,2H),2.77(brt, 2H),1.9–1.7(m,3H), 1.21(m, 2H). 37.4-{[(1H-Imidazole-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacidbenzyl ester

¹H NMR (δ, CDCl₃):7.58(m, 2H), 7.38–7.27(m, 5H), 5.10(s,2H), 4.20(brd,2H),3.37(brs, 2H), 2.77(brt,2H), 1.9–1.7(m,3H), 1.21(m, 2H). 38.4-{[(1-Methyl-1H-pyrrole-2-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacidbenzyl ester

¹H NMR (δ, CDCl₃):7.38–7.25(m, 5H),6.71(m, 1H), 6.50(m,1H), 6.08(m,1H),6.00(brt, 1H),5.11(s, 2H), 4.22(brs,2H), 3.94(s, 3H),3.26(brs,2H),2.77(brt, 2H), 1.9–1.7(m, 3H), 1.21(m, 2H). 39.4-{[(5-Methyl-3H-imidazole-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacidbenzyl ester

¹H NMR (δ, CDCl₃):9.62(brs, 1H), 7.40(s,1H), 7.31(m, 6H),5.12(s, 2H),4.19(brd,2H), 3.25(brs,2H), 2.77(brt, 2H),2.59(s, 3H), 1.9–1.7(m, 3H),1.21(m, 2H). 40.4-{[(1H-Pyrrole-3-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacidbenzyl ester

¹H NMR (δ, CDCl₃):8.55(brs, 1H), 7.28(m,6H), 6.78(s, 1H),6.40(s, 1H),5.88(brt,1H), 5.10(s, 2H),4.19(brs, 2H), 3.30(brs,2H), 2.77(brt,2H),1.9–1.7(m, 3H),1.20(m, 2H). 41.4-{[(Thiophene-3-carbonyl)-amino]-methyl}-piperidine-1-carboxylic acid4-methyl-benzyl ester

¹H NMR (δ, CDCl₃):7.83(m, 1H), 7.38(m,2H), 7.24(d, 2H),7.18(d, 2H),6.19(brt,1H), 5.02(s, 2H),4.20(brs, 2H),3.30(brs, 2H),2.77(brt, 2H),2.35(s,3H), 1.9–1.7(m, 3H),1.21(m, 2H). 42.4-{[(2H-Pyrazole-3-carbonyl)-amino]-methyl}-piperidine-1-carboxylic acid4-fluoro-benzyl ester

¹H NMR (δ, CDCl₃):7.60(d, 1H), 7.30(d,2H), 7.04(m, 3H),6.82(d, 1H),5.04(s,2H), 4.18(brs, 2H),3.33(brs, 2H), 2.77(brt,2H), 1.9–1.7(m,3H),1.21(m, 2H). 43.4-{[(2H-Pyrazole-3-carbonyl)-amino]-methyl}-piperidine-1-carboxylic acid4-chloro-benzyl ester

¹H NMR (δ, CDCl₃):7.58(d, 1H), 7.27(m,4H), 7.04(brt, 1H),6.82(d, 1H),5.05(s,2H), 4.18(brs, 2H),3.36(brs, 2H), 2.77(brt,2H), 1.9–1.7(m,3H),1.21(m, 2H). 44.4-{[(2H-Pyrazole-3-carbonyl)-amino]-methyl}-piperidine-1-carboxylic acid4-methyl-benzyl ester

¹H NMR (δ, CDCl₃):7.60(d, 1H), 7.22(d,2H), 7.17 d, 2H), 6.97(brt,1H),6.84(d, 1H),,5.04(s, 2H), 4.20(brs,2H), 3.35(brs, 2H),2.77(brt,2H),2.37(m, 3H), 1.9–1.7(m, 3H), 1.21(m, 2H). 45.4-{[(1H-Pyrazole-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylic acid4-fluoro-benzyl ester

¹H NMR (δ, CDCl₃):7.94(s, 2H), 7.30(m,2H), 7.01(m, 2H),6.60(brs, 1H),5.03(s,2H), 4.16(brd, 2H),3.24(brs, 2H),2.75(brs, 2H), 1.9–1.7(m, 3H),1.15(m, 2H). 46.4-{[(1H-Pyrazole-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylic acid4-chloro-benzyl ester

¹H NMR (δ, CDCl₃):7.94(s, 2H), 7.26(m,4H), 6.43(brs, 1H),5.03(s, 2H),4.17(brs,2H), 3.25(brs, 2H),2.77(brs, 2H), 1.9–1.7(m, 3H), 1.15(m, 2H).47. 4-{[(1H-Pyrazole-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacid 4-methyl-benzyl ester

¹H NMR (δ, CDCl₃):7.94(s, 2H), 7.25(d,2H), 7.16(d, 2H),6.03(brt, 1H),5.06(s,2H), 4.20(brs, 2H),3.30(brs, 2H), 2.77(brt,2H), 2.37(s,3H),1.9–1.7(m, 3H),1.20(m, 2H). 48.4-{[(1H-Pyrazole-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacidindan-2-yl ester

¹H NMR (δ, CDCl₃):7.94(s, 2H), 7.20(m,4H), 6.15(brt, 1H),5.42(m, 1H),4.10(brd,2H), 3.30(m, 4H),3.00(dd, 2H), 2.70(t,2H), 1.8–1.6(m,3H),1.18(m, 2H). 49.4-{[(1H-Pyrrole-2-carbonyl)-amino]-methyl}-piperidine-1-carboxylic acid4-methyl-benzyl ester

¹H NMR (δ, CDCl₃):9.43(brs, 1H), 7.24(d,2H), 7.17(d, 2H),6.91(s, 1H),6.55(s,1H), 6.22(m, 1H),5.95(brt, 1H), 5.06(s,2H), 4.19(brs,2H),3.30(brs, 2H),2.77(brt, 2H), 2.36(s,3H), 1.9–1.7(m,3H), 1.18(m, 2H).

EX. Name Structure Data 50.4-{[(1H-Imidazole-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacid 4-chloro-benzyl ester

¹H NMR(δ, CDCl₃):7.59(s, 2H), 7.30(m,5H), 5.06(s, 2H),4.18(brs, 2H),3.33(brs, 2H), 2.77(brt,2H), 1.9–1.7(m, 3H),1.21(m, 2H). 51.4-{[(1-Methyl-1H-pyrrole-2-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacid 4-fluoro-benzyl ester

¹H NMR(δ, CDCl₃):7.31(dd, 2H), 7.02(dd, 2H), 6.72(s,1H), 6.50(m,1H),6.08(m, 1H), 6.00(brt, 1H), 5.04(s,2H), 4.18(brs, 2H),3.93(s, 3H),3.25(brs, 2H), 2.77(brt,2H), 1.9–1.7(m, 3H),1.18(m, 2H). 52.4-{[(1H-Pyrrole-2-carbonyl)-amino]-methyl}-piperidine-1-carboxylic acid4-chloro-benzyl ester

¹H NMR(δ, CDCl₃):9.37(brs, 1H), 7.24(m, 4H), 6.92(s, 1H), 6.53(s, 1H),6.22(m,1H), 5.93(brt, 1H),5.06(s, 2H), 4.20(brs, 2H), 3.31(brs,2H),2.77(brt, 2H),1.9–1.7(m, 3H), 1.18(m, 2H). 53.4-{[(2-Methyl-1H-pyrrole-3-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacid 4-methyl-benzyl ester

¹H NMR(δ, CDCl₃):8.10(brs, 1H), 7.25(d, 2H), 7.17(d, 2H),6.59(m, 1H),6.23(m, 1H), 5.81(brt,1H), 5.06(s, 2H),4.20(brs, 2H), 3.26(brs, 2H),2.77(brt,2H), 2.55(s, 3H),2.36(s, 3H), 1.9–1.7(m, 3H), 1.20(m,2H). 54.4-{[(1H-Pyrrole-3-carbonyl)-amino]-methyl}-piperidine-1-carboxylic acid4-methyl-benzyl ester

¹H NMR(δ, CDCl₃):8.55(brs, 1H), 7.36(m, 1H), 7.25(d, 2H),7.17(d, 2H),6.77(m,1H), 6.40(m, 1H),5.86(brt, 1H), 5.06(s, 2H), 4.19(brs,2H),3.29(brs, 2H),2.77(brt, 2H), 2.36(s,3H), 1.9–1.7(m, 3H),1.18(m, 2H). 55.4-{[(Thiazole-5-carbonyl)-amino]-methyl}-piperidine-1-carboxylic acid4-methyl-benzyl ester

¹H NMR(δ, CDCl₃):8.90(s, 1H), 8.24(s,1H), 7.24(d, 2H),7.16(d, 2H),6.24(brt, 1H), 5.05(s,2H), 4.20(brs, 2H),3.35(brs, 2H), 2.77(brt, 2H),2.36(s,3H), 1.9–1.7(m, 3H),1.21(m, 2H). 56.4-{[(Oxazole-5-carbonyl)-amino]-methyl}-piperidine-1-carboxylic acid4-methyl-benzyl ester

¹H NMR(δ, CDCl₃):7.90(s, 1H), 7.72(s,1H), 7.23(d, 2H),7.17(d, 2H),6.35(brt, 1H), 5.05(s,2H), 4.20(brs, 2H),3.33(brs, 2H), 2.77(brt, 2H),2.35(s,3H), 1.9–1.7(m, 3H),1.20(m, 2H). 57.4-{[(1H-Pyrazole-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylic acid4-isopropyl-benzylester

¹H NMR(δ, CDCl₃):7.93(s, 2H), 7.25(m,4H), 6.62(brt, 1H),5.07(s, 2H),4.16(brd, 2H), 3.26(brs,2H), 2.89(m, 1H),2.71(brt, 2H), 1.9–1.7(m, 3H),1.23(d, 6H),1.18(m, 2H). 58.4-{[(1H-Pyrazole-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacidthiophen-3-ylmethylester

¹H NMR(δ, CDCl₃):10.50(brs, 1H), 7.94(s, 2H), 7.28(m, 2H),7.08(m, 1H),5.93(brt, 1H), 5.11(s,2H), 4.19(brs, 2H),3.31(brs, 2H), 2.77(brt, 2H),1.9–1.7(m,3H), 1.19(m, 2H). 59.4-[(4-Hydroxy-benzoylamino)-methyl]-piperidine-1-carboxylic acid4-isopropyl-benzylester

¹H NMR(δ,CD₃OD): 8.24(brd,1H) 7.68(d, 2H),7.20(m, 4H), 6.79(d,2H),5.02(s, 2H),4.10(d, 2H), 3.20(t,2H), 2.81(m, 1H),2.77(brs, 2H), 1.77(m,1H), 1.70(brd,2H), 1.20(d, 6H),1.16(m, 2H). 60.4-[(4-Hydroxy-benzoylamino)-methyl]-piperidine-1-carboxylicacidthiophen-3-ylmethylester

¹H NMR(δ, CDCl₃):7.94(s, 2H), 7.26(m,4H), 7.09(d, 1H), 5.92(brt, 1H),5.14(s, 2H), 4.19(brs,2H), 3.30(brs, 2H),2.77(brt, 2H), 1.9–1.7(m, 3H),1.20(m,2H). 61.4-{[(Pyridine-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylic acid4-isopropyl-benzylester

¹H NMR(δ, CDCl₃):8.72(d, 2H), 7.60(d,2H), 7.22(m, 4H),6.55(brt, 1H),5.06(s, 2H), 4.21(brd,2H), 3.33(brs, 2H),2.90(m, 1H), 2.77(brt, 2H),1.9–1.7(m,3H), 1.21(d, 6H),1.18(m, 2H). 62.4-{[(2H-Pyrazole-3-carbonyl)-amino]-methyl}-piperidine-1-carboxylic acid4-isopropyl-benzylester

¹H NMR(δ, CDCl₃):7.57(m, 1H), 7.23(m, 4H), 7.02(brt,1H), 6.83(m,1H),5.06(s, 2H), 4.19(brs, 2H), 3.33(brs,2H), 2.90(m, 1H),2,77(brt, 2H),1.9–1.7(m, 3H), 1.21(d, 6H),1.18(m, 2H). 63.4-{[(1H-Pyrrole-3-carbonyl)-amino]-methyl}-piperidine-1-carboxylic acid4-isopropyl-benzylester

¹H NMR(δ, CDCl₃):9.79(brs, 1H), 7.30–7.15(m, 5H), 6.70(s,1H), 6.42(s,1H),6.30(brt, 1H), 5.06(s, 2H), 4.17(brs,2H), 3.25(brs, 2H),2.90(m, 1H),2.75(brs, 2H), 1.9–1.7(m,3H), 1.22(d, 6H),1.17(m, 2H). 64.4-Hydroxy-N-[1-(3-phenyl-propionyl)-piperidin-4-ylmethyl]-benzamide

¹H NMR(δ, CDCl₃):8.80(brs, 1H), 7.63(d, 2H), 7.3–7.1(m,5H), 6.89(d,2H),6.69(brt, 1H), 4.58(d, 1H), 3.76(d, 1H),3.35–3.18(m, 2H),2.90(m,3H), 2.60(t,2H), 2.49(t, 1H), 1.9–1.7(m, 3H), 1.1–0.9(m, 2H). 65.4-{[(2-Chloro-pyridine-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacidbenzyl ester

M.S. (M⁺ + 1) 388 66.4-{[(6-Amino-pyridine-3-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacidbenzyl ester

M.S. (M⁺ + 1) 369 67. 4-(Benzoylamino-methyl)-piperidine-1-carboxylicacidbenzyl ester

M.S. (M⁺ + 1) 353 68.4-[(3-Cyano-benzoylamino)-methyl]-piperidine-1-carboxylic acidbenzylester

M.S. (M⁺ + 1) 378 69.4-{[(Pyridine-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacidindan-2-yl ester

M.S. (M⁺ + 1) 380 70.4-{[(2-Amino-pyridine-3-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacidbenzyl ester

M.S. (M⁺ + 1) 369 71.4-[(4-Methylamino-benzoylamino)-methyl]-piperidine-1-carboxylicacidbenzyl ester

M.S. (M⁺ + 1) 382 72.4-[(4-Amino-benzoylamino)-methyl]-piperidine-1-carboxylic acidbenzylester

M.S. (M⁺ + 1) 368 73.4-[(4-Trifluoromethoxy-benzolyamino)-methyl]-piperidine-1-carboxylicacidbenzyl ester

M.S. (M⁺ + 1) 437 74.4-[(4-Fluoro-benzoylamino)-methyl]-piperidine-1-carboxylic acidbenzylester

M.S. (M⁺ + 1) 371 75.4-[(2-Amino-benzoylamino)-methyl]-piperidine-1-carboxylic acidbenzylester

M.S. (M⁺ + 1) 368 76.4-{[(5-Ethyl-2-methyl-2H-pyrazole-3-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacidbenzyl ester

M.S. (M⁺ + 1) 385 77.4-{[(6-Chloro-imidazo[1,2-a]pyridine-2-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacidbenzyl ester

M.S. (M⁺ + 1) 427 78.4-{[(4-Bromo-thiophene-3-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacidbenzyl ester

M.S. (M⁺ + 1) 438 79.4-{[(Isoxazole-5-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacidbenzyl ester

M.S. (M⁺ + 1) 344 80.4-{[(1H-Imidazole-2-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacidbenzyl ester

M.S. (M⁺ + 1) 343 81.4-{[(3-Bromo-pyridine-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacidbenzyl ester

M.S. (M⁺ + 1) 433 82.4-{[([1,6]-Naphthyridine-2-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacidbenzyl ester

M.S. (M⁺ + 1) 405 83.4-{[(1-Methyl-1H-imidazole-2-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacidbenzyl ester

M.S. (M⁺ + 1) 357 84.4-{[(5-Bromo-pyridine-3-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacidbenzyl ester

M.S. (M⁺ + 1) 432 85.4-{[(Isoxazole-3-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacidbenzyl ester

M.S. (M⁺ + 1) 344 86.4-{[(6-Bromo-pyridine-3-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacidbenzyl ester

M.S. (M⁺ + 1) 432 87.4-{[(2-Methyl-thiazole-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacidbenzyl ester

M.S. (M⁺ + 1) 374 88.4-{[(Oxazole-5-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacidbenzyl ester

M.S. (M⁺ + 1) 344 89.4-{[(Pyrimidine-2-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacidbenzyl ester

M.S. (M⁺ + 1) 355 90.4-{[(1,4,5,6-Tetrahydro-cyclopentapyrazole-3-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacidbenzyl ester

M.S. (M⁺ + 1) 383 91.4-{[(2-Methylsulfanyl-thiazole-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacidbenzyl ester

M.S. (M⁺ + 1) 406 92.4-{[(5-Methyl-thiazole-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacidbenzyl ester

M.S. (M⁺ + 1) 374 93.4-{[(5-Methyl-2H-[1,2,4]triazole-3-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacidbenzyl ester

M.S. (M⁺ + 1) 358 94.4-{[(4-Phenyl-thiazole-2-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacidbenzyl ester

M.S. (M⁺ + 1) 436 95.4-{[(5-Hydroxymethyl-3H-imidazole-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacidbenzyl ester

M.S. (M⁺ + 1) 373 96.4-{[(2-Methyl-thiazole-5-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacidbenzyl ester

M.S. (M⁺ + 1) 374 97.4-{[(2-Methyl-1H-pyrrole-3-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacidbenzyl ester

M.S. (M⁺ + 1) 356 98.4-{[(2-Methyl-thiophene-3-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacidbenzyl ester

M.S. (M⁺ + 1) 373 99.4-{[(Thiophene-3-carbonyl)-amino]-methyl}-piperidine-1-carboxylic acid4-fluoro-benzyl ester

M.S. (M⁺ + 1) 377 100.4-{[(Thiophene-3-carbonyl)-amino]-methyl}-piperidine-1-carboxylic acid4-chloro-benzyl ester

M.S. (M⁺ + 1) 393 101.4-{[(Thiophene-3-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacidindan-2-yl ester

M.S. (M⁺ + 1) 385 102.4-{[(2H-Pyrazole-3-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacidindan-2-yl ester

M.S. (M⁺ + 1) 369 103.4-{[(1H-Imidazole-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacid 4-methyl-benzyl ester

M.S. (M⁺ + 1) 357 104.4-{[(1-Methyl-1H-pyrrole-2-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacid 4-methyl-benzyl ester

M.S. (M⁺ + 1) 370 105.4-{[(1H-Imidazole-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacid 4-fluoro-benzyl ester

M.S. (M⁺ + 1) 361 106.4-{[(1H-Imidazole-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacidindan-2-yl ester

M.S. (M⁺ + 1) 369 107.4-{[(1-Methyl-1H-pyrrole-2-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacid 4-chloro-benzyl ester

M.S. (M⁺ + 1) 390 108.4-{[(1-Methyl-1H-pyrrole-2-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacidindan-2-yl ester

M.S. (M⁺ + 1) 382 109.4-{[(1H-Pyrrole-2-carbonyl)-amino]-methyl}-piperidine-1-carboxylic acid4-fluoro-benzyl ester

M.S. (M⁺ + 1) 360 110.4-{[(1H-Pyrrole-2-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacidindan-2-yl ester

M.S. (M⁺ + 1) 368 111.4-{[(1H-Pyrazole-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylic acid4-bromo-thiophen-3-ylmethyl ester

M.S. (M⁺ + 1) 427 112.4-{[(Pyrazine-2-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacidbenzyl ester

M.S. (M⁺ + 1) 355 113.4-{[(Quinoline-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacidbenzyl ester

M.S. (M⁺ + 1) 404 114.4-{[(2,6-Dihydroxy-pyridine-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacidbenzyl ester

M.S. (M⁺ + 1) 386 115.4-{[(1-Oxy-pyridine-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacidbenzyl ester

M.S. (M⁺ + 1) 370 116.4-{[(Pyrimidine-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacidbenzyl ester

M.S. (M⁺ + 1) 355 117.4-{[(1-Methyl-1H-pyrazole-3-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacidbenzyl ester

M.S. (M⁺ + 1) 357 118.4-{[(2-Methyl-2H-pyrazole-3-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacidbenzyl ester

M.S. (M⁺ + 1) 357 119.4-{[(1-Methyl-1H-pyrazole-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacidbenzyl ester

M.S. (M⁺ + 1) 357 120.4-{[([1,2,5]-Thiadiazole-3-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacidbenzyl ester

M.S. (M⁺ + 1) 361 121.4-{[(5-Bromo-pyridine-2-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacidbenzyl ester

M.S. (M⁺ + 1) 432 122.4-{[(Pyrimidine-5-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacidbenzyl ester

M.S. (M⁺ + 1) 355 123.4-{[(Pyrazolo[1,5-a]-pyrimidine-3-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacidbenzyl ester

M.S. (M⁺ + 1) 394 124.4-{[(6-Bromo-pyridine-2-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacidbenzyl ester

M.S. (M⁺ + 1) 432 125.4-{[(Benzothiazole-2-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacidbenzyl ester

M.S. (M⁺ + 1) 410 126.4-{[(3,5-Dimethyl-1H-pyrrole-2-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacidbenzyl ester

M.S. (M⁺ + 1) 370 127.4-{[(3-Methyl-pyridine-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacidbenzyl ester

M.S. (M⁺ + 1) 368 128.4-{[(6-Cyano-pyridine-3-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacidbenzyl ester

M.S. (M⁺ + 1) 379 129.4-{[(2-Methyl-pyridine-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacidbenzyl ester

M.S. (M⁺ + 1) 368 130.4-{[(2-Methoxy-6-methyl-pyridine-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacidbenzyl ester

M.S. (M⁺ + 1) 398 131.4-{[(2-Chloro-6-methyl-pyridine-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacidbenzyl ester

M.S. (M⁺ + 1) 402 132.4-{[(6-Amino-pyridazine-3-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacidbenzyl ester

M.S. (M⁺ + 1) 370 133.4-[(2-Hydroxy-benzoylamino)-methyl]-piperidine-1-carboxylic acidbenzylester

M.S. (M⁺ + 1) 369 134.4-[(3-Hydroxy-benzoylamino)-methyl]-piperidine-1-carboxylic acidbenzylester

M.S. (M⁺ + 1) 369 135.4-[(2,5-Dihydroxy-benzoylamino)-methyl]-piperidine-1-carboxylicacidbenzyl ester

M.S. (M⁺ + 1) 385 136.4-[(4-Hydroxy-3,5-diiodo-benzoylamino)-methyl]-piperidine-1-carboxylicacidbenzyl ester

M.S. (M⁺ + 1) 621

Example 137 1H-Pyrazole-4-carboxylic acid[1-(3-phenyl-propionyl)-piperidin-4-ylmethyl]-amide

Step 1:

1H-Pyrazole-4-carboxylic acid (piperidin-4-ylmethyl)-amide

4-{[(1H-Pyrazole-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylic acidbenzyl ester (EXAMPLE 34) (600 mg, 1.75 mmol), 10% palladium on Carbon(150 mg) and ethanol (15 mL) were combined in a Parr® jar andhydrogenated at 50 psi for 24 h. The reaction mixture was filteredthrough Celite® and the filtrate was evaporated in vacuo to give theproduct as a white foam.

Step 2:

1H-Pyrazole-4-carboxylic acid[1-(3-phenyl-propionyl)-piperidin-4-ylmethyl]-amide

1H-Pyrazole-4-carboxylic acid (piperidin-4-ylmethyl)-amide (352 mg, 1.69mmol), hydrocinnamoyl chloride (503 μL, 3.38 mmol),diisopropylethylamine (294 μL, 1.69 mmol) and DMF (4 mL) were combinedunder Nitrogen and stirred at 25° C. for 24 h. Sodium hydroxide (1 mL,2N) was added and the mixture was stirred 1 h. Water was added and thecontents of the reaction flask were extracted with EtOAc (3×50 mL). Thecombined organic extracts were dried with Na₂SO₄ and filtered. Thefiltrate was removed in vacuo and the remaining residue was purifiedusing an ISCO® normal phase silica chromatography system (CH₂Cl₂ (100%)to CH₂Cl₂:MeOH:NH₄OH 90:10:1). Fractions containing the desired productwere combined and the solvent was removed in vacuo to give a colorlessoil. Addition of EtOAc followed by 1N HCl/Et₂O gave the product as awhite solid.

¹H NMR (500 MHz, δ, DMSO-d₆): 8.10 (m, 1H), 8.04 (s, 2H), 7.28–7.20 (m,4H), 7.18–7.14 (m, 1H), 4.38 (m, 1H), 3.85 (m, 1H), 3.06 (m, 2H), 2.90(m, 1H), 2.80 (t, 2H), 2,60 (m, 2H), 1.75–1.60 (m, 4H), 0.95 (m, 2H).

The following compounds were prepared by substituting the appropriateacid chloride for the hydrocinnamoyl chloride in the above procedure.

EX. Name Structure Analytical Data 138 1H-Pyrazole-4-carboxylic acid[1-(2-phenyl-cyclopropane-carbonyl)-piperidin-4-ylmethyl]-amide

¹H NMR(500MHz,δ, DMSO-d₆):8.08–7.98(m, 3H), 7.26(m, 2H), 7.17(m,3H),4.38(m, 1H),4.16(m, 1H), 3.15–2.97(m, 3H), 2.58(m, 1H), 2.26(m,2H),1.80–1.60(m,3H), 1.30(m, 1H),1.20–0.95(m, 3H). 1391H-Pyrazole-4-carboxylic acid[1-(3-phenyl-acryloyl)-piperidin-4-ylmethyl]-amide

¹H NMR(500MHz,δ, DMSO-d₆): 8.16(s, br, 1H), 8.07(m,1H), 7.88(s, br,1H),7.70(m, 2H), 7.48–7.34(m, 4H), 7.26(m, 2H), 4.48(m,1H), 4.29(m,1H),3.17–3.00(m, 3H),2.65(m, 1H), 1.85–1.69(m, 3H), 1.15–1.00(m, 2H).The following examples were prepared from 1H-pyrazole4-carboxylic acid(piperidin-4-ylmethyl)-amide as described in Example 1 Step 2.

EX. Name Structure Analytical Data 140[1-Benzyl-2-oxo-2-(4-{[(1H-pyrazole-4-carbonyl)-amino]-methyl}-piperidin-1-yl)-ethyl]-carbamicacidtert-butyl ester

M.S. (M⁺ + 1) 456 141[1-(4-Chloro-benzyl)-2-oxo-2-(4-{[(1H-pyrazole-4-carbonyl)-amino]-methyl}-piperidin-1-yl)-ethyl]-carbamicacid tert-butyl ester

M.S. (M⁺ + 1) 490 142 1H-Pyrazole-4-carboxylic acid[1-(2-hydroxy-3-phenyl-propionyl)-piperidin-4-ylmethyl]-amide

M.S. (M⁺ + 1) 357 143 1H-Pyrazole-4-carboxylic acid[1-(2-methyl-3-phenyl-propionyl)-piperidin-4-ylmethyl]-amide

M.S. (M⁺ + 1) 355 144 1H-Pyrazole-4-carboxylic acid{1-[2-hydroxy-3-(4-hydroxy-phenyl)-propionyl]-piperidin-4-ylmethyl}-amide

M.S. (M⁺ + 1) 373 145 1H-Pyrazole-4-carboxylic acid[1-(2-phenyl-cyclopropane-carbonyl)-piperidin-4-ylmethyl]-amide

M.S. (M⁺ + 1) 353The following two compounds were prepared from EXAMPLES 140 and 141respectively by treatment with trifluoroacetic acid in dichloromethane.

EX. Name Structure Analytical Data 146 1H-Pyrazole-4-carboxylic acid[1-(2-amino-3-phenyl-propionyl)-piperidin-4-ylmethyl]-amide

M.S. (M⁺ + 1) 356 147 1H-Pyrazole-4-carboxylic acid{1-[2-amino-3-(4-chloro-phenyl)-propionyl]-piperidin-4-yl-methyl}-amide

M.S. (M⁺ + 1) 390

Example 148 Trans 1H-Pyrazole-4-carboxylic acid[1-(2-phenyl-cyclopropylmethyl)-piperidin-4-ylmethyl]-amide

A solution of 1H-pyrazole-4-carboxylic acid (piperidin-4-ylmethyl)-amide(290 mg, 1.39 mmol), trans-2-phenylcyclopropanecarbaldehyde (224 mg,1.53 mmol) and sodium triacetoxyborohydride (590 mg, 2.78 mmol) in MeOH(15 mL) was heated to 50° C. and stirred for 1 h. The resulting reactionmixture was concentrated and purified by silica gel chromatography(gradient: CH₂Cl₂ to 80:20:2 CH₂Cl₂:MeOH:NH₄OH) to give the trans1H-pyrazole-4-carboxylic acid[1-(2-phenyl-cyclopropylmethyl)-piperidin-4-ylmethyl]-amide product.

¹H NMR (δ, CDCl₃): 7.86 (s, 2H), 7.23 (d, 2H), 7.17 (t, 1H), 7.02 (d,2H), 5.94 (brt, 1H), 3.35 (m, 2H), 3.10 (brt, 2H), 2.55 (dd, 1H), 2.39(dd, 1H), 2.30 (q, 2H), 1.70–1.55 (m, 4H), 1.41 (m, 2H), 1.22 (m, 1H),0.95 (m, 1H), 0.82 (m, 1H).

The following compounds were prepared similarly to the proceduredescribed above for EXAMPLE 148 but substituting the appropriatealdehyde for the trans-2-phenylcyclopropanecarbaldehyde.

EX. Name Structure Analytical Data 149 1H-Pyrazole-4-carboxylic acid[1-(3-phenyl-propyl)-piperidin-4-ylmethyl]-amide

¹H NMR(δ, CDCl₃):7.93(s, 2H), 7.3–7.15(m, 5H), 6.30(brt, 1H),3.35(t,2H), 3.04(brd, 2H),2.61(t, 2H), 2.46(dd, 2H), 2.04(t,2H), 1.88(m,2H),1.70(m, 2H), 1.47(m, 2H), 1.27(t,1H). 150 1H-Pyrazole-4-carboxylicacid [1-(4-phenyl-butyl)-piperidin-4-ylmethyl]-amide

¹H NMR(δ, CD₃-OD): 8.03(s, 2H),7.3–7.1(m, 5H),3.21(d, 2H), 2.97(brd,2H), 2.63(t,2H), 2.40(dd, 2H),2.01(t, 2H), 1.76(brd, 2H), 1.7–1.5(m,5H), 1.30(m,2H). 151 1H-Pyrazole-4-carboxylic acid(1-phenethyl-piperidin-4-ylmethyl)-amide

M.S. (M⁺ + 1) 313 152 1H-Pyrazole-4-carboxylic acid[1-(2-phenyl-cyclopropyl-methyl)-piperidin-4-ylmethyl]-amide

M.S. (M⁺ + 1) 339 153 1H-Pyrazole-4-carboxylic acid[1-(2-phenyl-cyclopropyl-methyl)-piperidin-4-ylmethyl]-amide

¹H NMR(δ, CDCl₃):7.86(s, 2H), 7.23(d,2H), 7.17(t, 1H),7.00(d, 2H),6.61(brs, 1H), 3.30(m,2H), 3.10(brt, 2H),2.55(dd, 1H), 2.39(dd, 1H),2.03(q,2H), 1.70–1.55(m,4H), 1.41(m, 2H),1.22(m, 1H), 0.95(m, 1H),0.82(m,1H).

The following compounds were prepared as described above for EXAMPLE148, but replacing 1H-pyrazole-4-carboxylic acid(piperidin-4-ylmethyl)-amide with, for example,4-hydroxy-N-piperidin-4-ylmethyl-benzamide, which was prepared from4-[(4-hydroxy-benzoylamino)-methyl]-piperidine-1-carboxylic acid benzylester as described in EXAMPLE 137, step 1.

EX. Name Structure Analytical Data 1544-Hydroxy-N-[1-(2-phenyl-cyclopropyl-methyl)-piperidin-4-ylmethyl]-benzamide

¹H NMR(δ, CDCl₃):7.43(d, 2H), 7.3–7.1(m, 3H), 7.00(d,2H), 6.65(d,2H),6.39(brt, 1H), 3.35(m, 2H), 3.14(brt,2H), 2.58(dd, 1H),2.41(dd, 1H),2.08(q, 2H), 1.7–1.5(m,4H), 1.41(m, 2H),1.22(m, 1H), 0.96(m, 1H),0.82(m,1H). 1554-Hydroxy-N-[1-(3-phenyl-propyl)-piperidin-4-ylmethyl]-benzamide

¹H NMR(δ, CD₃-OD): 7.70(d, 2H),7.3–7.1(m, 5H),6.80(d, 2H), 3.23(d, 2H),3.02(brd,2H), 2.61(dd, 2H),2.42(dd, 2H), 2.08(brt, 2H), 1.9–1.6(m, 5H),1.35(m,2H).

Example 1564-{[(Pyridine-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylic acid4-cyclopropyl-benzyl ester

Step 1:

4-Cyclopropyl-benzoic acid ethyl ester

Indium trichloride (2.2 g, 10 mmol) and THF (50 mL) were combined undernitrogen and cooled to −70° C. Cyclopropylmagnesium bromide solution (33mL, 30 mmol, 0.92M) was added dropwise while maintaining the reactiontemperature ≦−60° C. After the addition was complete the reaction wasstirred 0.5 h with cooling then 0.5 h with the cooling bath removed. Theresulting solution was added via cannula to a refluxing solution ofethyl-4-iodobenzoate (5.5 g, 20 mmol),trans-dichlorobis(triphenylphosphine)palladium(II) (421 mg, 0.60 mmol)and THF (100 mL) under nitrogen. After 24 h, the contents of thereaction flask were cooled and the solvent was removed in vactio. Water(100 mL) and 5% KHSO₄ were added and the mixture was extracted withCH₂Cl₂ (3×100 mL). The combined organic extracts were washed with brine,dried with Na₂SO₄ and filtered. The filtrate was removed in vacuo andthe remaining residue was purified by flash column chromatography(hexane:EtOAc 95:5) to give the 4-cyclopropyl-benzoic acid ethyl esteras an orange oil.

Step 2:

(4-Cyclopropyl-phenyl)-methanol

4-Cyclopropyl-benzoic acid ethyl ester (2.46 g, 13 mmol), and THF (250mL) were combined under nitrogen and cooled in an IPA/dry ice bath to−70° C. Lithium aluminum hydride solution (20 mL, 20 mmol, 1.0M) wasadded dropwise. After 2 h excess lithium aluminum hydride was quenchedby adding EtOAc dropwise. The reaction was warmed to 25° C. then thesolvent was removed in vacuo. Water (200 mL) and a few drops of HCl(aq,6N) were added. The mixture was extracted with EtOAc (3×100 mL). Thecombined organic extracts were washed with brine, dried with Na₂SO₄ andfiltered. The filtrate was removed in vacuo and the remaining residuewas purified by flash column chromatography (hexane:EtOAc 40:60) to givethe (4-cyclopropyl-phenyl)-methanol as a colorless oil.

Step 3:

Carbonic acid 4-cyclopropyl-benzyl ester 2,5-dioxo-pyrrolidin-1-yl ester

The title compound was prepared from (4-Cyclopropyl-phenyl)-methanol asdescribed above for similar compounds (Chem. Pharm. Bull., 38(1):110–115(1990)).

Step 4:

4-Aminomethyl-piperidine-1-carboxylic acid 4-cyclopropyl-benzyl ester

The title compound was prepared from carbonic acid 4-cyclopropyl-benzylester 2,5-dioxo-pyrrolidin-1-yl ester as described in EXAMPLE 1, Step 1.

Step 5:

4-{[(Pyridine-4-carbonyl)amino]-methyl}-piperidine-1-carboxylic acid4-cyclopropyl-benzyl ester

The title compound was prepared from4-aminomethyl-piperidine-1-carboxylic acid 4-cyclopropyl-benzyl ester asdescribed above in EXAMPLE 1, Step 2.

M.S. (M⁺+1) 394

The following compounds were prepared from4-aminomethyl-piperidine-1-carboxylic acid 4-cyclopropyl-benzyl ester asdescribed above in EXAMPLE 1, step 2.

EX. Name Structure Analytical Data 1574-[(4-Hydroxy-ben-zoylamino)-methyl]-piperidine-1-carboxy-lic acid4-cyclopropyl-benzyl ester

M.S. (M⁺ + 1) 409 1584-{[(1H-Pyrazole-3-carbonyl)-amino]-methyl}-piperidine-1-carboxylic acid4-cyclopropyl-benzylester

M.S. (M⁺ + 1) 383 1594-{[(1H-Pyrazole-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylic acid4-cyclopropyl-benzylester

¹H NMR(500MHzδ, CDCl₃): 10.70(s,br, 1H), 7.95(s, 2H),7.25(d, 2H),7.05(d,2H), 600(m, 1H),5.06(s, 2H), 4.20(s,br, 2H), 3,30(s, br,2H),2.75(s, br, 2H),1.90(m, 1H), 1.85–1.50(m, 3H), 1.20m, 2H), 0.97(m,2H),0.68(m, 2H).

The following compounds were prepared from4-hydroxy-N-piperidin-4-ylmethyl-benzamide (prepared from4-[(4-hydroxy-benzoylamino)-methyl]-piperidine-1-carboxylic acid benzylester as described in EXAMPLE 137, step 1) as described in EXAMPLE 1,Step 2.

EX. Name Structure Analytical Data 1604-Hydroxy-N-[1-(2-phenyl-cyclopropane-carbonyl)-piperidin-4-ylmethyl]-benzamide

¹H NMR9 (δ, CDCl₃):8.72 (brs, 1H), 7.61(d, 2H), 7.24 (m,2H), 7.19 (t,1H),7.06 (d, 2H), 6.93 (d,2H), 6.72 (brs, 1H),4.55 (brd, 1H), 4.10(brd,1H) 3.3–3.1(m, 2H), 3.01 (q,1H), 2.58 (brt, 1H),2.41 (brs, 1H), 2.0–1.6(m, 5H), 1.3–1.1(m, 3H). 1614-Hydroxy-N-[1-(2-phenyl-cyclopropane-carbonyl)-piperidin-4-ylmethyl]-benzamide

M.S. (M⁺ + 1) 379

Example 162 1H-Pyrazole-4-carboxylic acid(1-benzylthiocarbamoyl-piperidin-4-ylmethyl)-amide

1H-Pyrazole-4-carboxylic acid (piperidin-4-ylmethyl)-amide (EXAMPLE 137,Step 1) (50 mg, 0.24 mmol), benzyl isothiocyanate (35 μL, 0.264 mmol)and DMF (1 mL) were combined and stirred under Nitrogen for 1 h. Thecontents of the reaction flask were poured into water and sodiumhydroxide (2 mL, 2N) was added. The resulting mixture was extracted withEtOAc (3×50 mL) and the combined organic extracts were dried withNa₂SO₄. The filtrate was removed in vacuo and the remaining residue waspurified by Gilson® reverse phase preparative HPLC. The fractioncontaining the desired product was evaporated in vacuo to give acolorless oil. Trituration with EtOAc/EtOH afforded the EXAMPLE 162 as awhite solid.

¹H NMR (500 MHz, δ, DMSO-d₆): 13.10 (s, 1H), 8.20 (m, 2H), 8.10 (m, 1H),7.90 (m, 1H), 7.32–7.18 (m, 5H), 4.80 (d, 2H), 4.65 (d, 2H), 3.10 (t,2H), 2.97 (t, 2H), 1.80 (m, 1H), 1.67 (m, 2H), 1.10 (m, 2H).

Example 1634-{[(1H-Pyrazole-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylic acidbenzylamide

The title compound was prepared as described in EXAMPLE 162 except thatbenzyl isocyanate was used instead of benzyl isothiocyanate.

¹H NMR (500 MHz, δ, DMSO-d₆): 13.10 (s, 1H), 8.16 (s, 1H), 8.04 (m, 1H),7.88 (s, 1H), 7.30–7.16 (m, 4H), 7.02 (m, 1H), 4.21 (d, 2H), 3.99 (d,2H), 3.10 (t, 2H), 2.65 (m, 2H), 1.72–1.58 (m, 3H), 1.05–0.95 (m, 2H).

Example 164 1H-Pyrazole-4-carboxylic acid[1-(2-hydroxy-3-phenyl-propyl)-piperidin-4-ylmethyl]-amide

To a solution of 2-benzyloxirane (0.01 mL, 0.07 mmol) in iso-propylalcohol (5 mL) was added 1H-pyrazole-4-carboxylic acid(piperidin-4-ylmethyl)-amide (EXAMPLE 137, Step 1) (15 mg, 0.07 mmol).The resulting reaction mixture was heated to 60° C. for 24 h. Thereaction mixture was concentrated, partitioned between EtOAc and aqueoussodium bicarbonate. The organic phase was dried, the solvent evaporated,and the crude product purified by reverse phase HPLC to give1H-Pyrazole-4-carboxylic acid[1-(2-hydroxy-3-phenyl-propyl)-piperidin-4-ylmethyl]-amide.

M.S. (M⁺+1) 343

Example 165

4-{[(2-Oxo-1,2-dihydro-pyridine-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacid benzyl ester

To 4-{[(-oxy-pyridine-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacid benzyl ester (EXAMPLE 115) (200 mg, 0.542 mmol) was added aceticanhydride (5 mL) and the mixture heated to reflux for 24 h. The reactionwas concentrated and chromatographed on silica using ethyl acetate togive an oil (40 mg). The crude material was dissolved in methanol (10mL) and treated with solid potassium carbonate (40 mg) for 0.5 h.Concentration of the reaction and extraction into dichloromethane (20mL) from aqueous sodium bicarbonate (20 mL) followed by concentrationand precipitation of the solid from ether gave the4-{[(2-Oxo-1,2-dihydro-pyridine-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacid benzyl ester.

M.S. (M+1): 370

Example 1664-{[(2-Methylaminomethyl-pyridine-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacid benzyl ester

Step 1:

Preparation of 2,4-pyridinedicarboxcyclic acid diethyl ester

To a mixture of 2,4-pyridinedicarboxylic acid (23 g, 0.138 mol) inethanol (500 mL) was bubbled anhydrous hydrogen chloride gas over aperiod of 6 h. The resulting reaction mixture was concentrated in vacuoand extracted into dichloromethane (500 mL) from 10% aqueous sodiumbicarbonate (500 mL). The organic extract was dried over sodium sulfate,and concentrated in vacuo to give 2,4-pyridinedicarboxcyclic aciddiethyl ester as an oil.

M.S. (M+1): 224

Step 2:

Preparation of 2-Formyl-isonicotinic acid ethyl ester

To a solution of 2,4-pyridinedicarboxcyclic acid diethyl ester (25 g,0.112 mol) in tetrahydrofuran (IL) at −78° C. and under nitrogen wasslowly added a solution of 1.0M diisobutylaluminum hydride in TF (11mL). The reaction was stirred at −78° C. for 5 h and then quenched byaddition of a solution of tetrahydrofuran-acetic acid-water (174 mL, 62mL, 15 mL) and the reaction allowed to warm to room temperature. Diethylether (500 mL) and 10% aqueous sodium bicarbonate (1 L) were added andthe mixture stirred for 0.5 h. The ether layer was removed and theaqueous layer extracted with ethyl acetate (4×500 mL) The combinedorganic extracts were washed with saturated sodium chloride andconcentrated to an oil which was purified by silica gel columnchromatography using 30%ethyl acetate/hexane as eluent to give2-formyl-isonicotinic acid ethyl ester as an oil.

M.S. (M+1): 180

Step 3:

Preparation of 2-Diethoxymethyl-isonicotinic acid ethyl ester

To a solution of 2-formyl-isonicotinic acid ethyl ester (5.0 g, 0.027mol) in ethanol (9 mL) was added triethyl orthoformate (6.2 mL, 0.037mol) followed by a solution of 6N hydrochloric acid in ethanol (1.5 mL).The mixture was heated to 110° C. (reflux) for 1.5 h, cooled to rt andsolid potassium carbonate (1.80 g) added. The mixture was stirred for 5min, concentrated in vacuo, and redissolved in diethyl ether (100 mL).The reaction was filtered through silica and the resulting cake washedwith diethyl ether (50 mL). The filtrated was concentrated in vacuo togive 2-diethoxymethyl-isonicotinic acid ethyl ester as an oil.

M.S. (M+1): 254

Step 4:

Preparation of 2-Diethoxymethyl-isonicotinic acid

To a solution of 2-diethoxymethyl-isonicotinic acid ethyl ester (3.0 g,0.012 mol) in tetrahydrofuran (100 mL) was added IN sodium hydroxide (24mL, 0.024 mol) and mixture allowed to stir for 2 h at rt. The reactionwas concentrated in vacuo to give a pasty solid of2-diethoxymethyl-isonicotinic acid, which was used in the next step asis.

M.S. (M+1): 226

Step 5:

Preparation of4-{[(2-Diethoxymethyl-pyridine-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacid benzyl ester

4-{[(2-Diethoxymethyl-pyridine-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacid benzyl ester was prepared in a similar manner as described inEXAMPLE 1, Step 2.

M.S. (M+1): 456

Step 6:

Preparation of4-{[(2-Formyl-pyridine-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacid benzyl ester

To a solution of4-{[(2-diethoxymethyl-pyridine-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacid benzyl ester (1.3 g, 0.0029 mol) in dioxane (20 mL) was added 1Nhydrochloric acid (40 mL) and the mixture was warmed to 50° C. for 1.5h. The reaction was cooled, diluted with ethyl acetate (100 mL) and 10%aqueous sodium bicarbonate (100 mL), and stirred well. The organic layerwas removed, dried over sodium sulfate, filtered and concentrated invacuo to give4-{[(2-formyl-pyridine-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacid benzyl ester as an oil.

M.S. (M+1): 382

Step 7:

Prep of4-{[(2-Methylaminomethyl-pyridine-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacid benzyl ester

To a solution of4-{[(2-formyl-pyridine-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacid benzyl ester (50 mg, 0.13 mmol) in dichloroethane (0.5 mL) wasadded acetic acid (8 μL, 0.13 mmol), 2.0 M methylamine in TEF (72 μL,0.14 mmol) followed by sodium triacetoxyborohydride (42 mg, 0.20 mmol).The resulting mixture was stirred for 5 h. The reaction was concentratedin vactio and the residue chromatographed (reverse phase C-18 usingacetonitrile/0.1% trifluoroacetic acid in water) to give uponconcentration in vacuo4-{[(2-methylaminomethyl-pyridine-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacid benzyl ester as the trifluoroacetic acid salt.

M.S. (m+1) 397

The following compounds were prepared as described above for4-{[(2-methylaminomethyl-pyridine-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacid benzyl ester, replacing methylamine with the appropriate amine instep 7, EXAMPLE 166.

EX. Name Structure Analytical Data 1674-{[(2-Dimethyl-aminomethyl-pyridine-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacidbenzyl ester

M.S. (M⁺ + 1) 411 1684-{[(2-Aminomethyl-pyridine-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacidbenzyl ester

M.S. (M⁺ + 1) 383

Example 1694-{[(2-Hydroxymethyl-pyridine-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacid benzyl ester

To a solution of4-{[(2-formyl-pyridine-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacid benzyl ester (EXAMPLE 166, Step 6) (50 mg, 0.131 mmol) in ethanol(2 mL) was added sodium borohydride (5 mg) and the mixture stirred for0.5 h. The reaction was diluted with 10% aqueous sodium bicarbonate (10mL) and extracted with ethyl acetate (25 mL). The ethyl acetate extractwas concentrated and chromatographed (reverse phase C-18 usingacetonitrile/0.1% trifluoroacetic acid in water) to give uponconcentration in vacuo the4-{[(2-hydroxymethyl-pyridine-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacid benzyl ester as the trifluoroacetic acid salt.

M.S. (M+1): 384

Example 1704-({[2-(1-Hydroxy-ethyl)-pyridine-4-carbonyl]-amino}-methyl)-piperidine-1-carboxylicacid benzyl ester

To a solution of4-{[(2-formyl-pyridine-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacid benzyl ester (EXAMPLE 166, Step 6) (50 mg, 0.131 mmol) in TBF (2mL) at −78° C. was added 3.0M methylmagnesium chloride (45 μL, 0.135mmol). The mixture was stirred for 5 min and allowed to warm to rt. Thereaction was diluted with 10% aqueous sodium bicarbonate (10 mL) andextracted with ethyl acetate (25 mL). The ethyl acetate extract wasconcentrated and chromatographed on silica using 100% ethyl acetate toethyl acetate/methanol (95/5) to give the4-({[2-(1-hydroxy-ethyl)-pyridine-4-carbonyl]-amino}-methyl)-piperidine-1-carboxylicacid benzyl ester.

M.S. (M⁺+1) 398

Example 1714-({[2-(2,4-Dimethoxy-benzylamino)-pyridine-4-carbonyl]-amino}-methyl)-piperidine-1-carboxylicacid benzyl ester

A mixture of4-{[(2-chloro-pyridine-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacid benzyl ester (EXAMPLE 65) (310 mg, 0.8 mmol) and2,4-dimethoxybenzylamnine (1 mL) were heated to 140° C. for 18 h, cooledto rt, and partitioned between pH5.2 citrate buffer and EtOAc. Theorganic layer was dried and the solvent evaporated to give the crudeproduct, purified by chromatography on silica (1:1 hexane EtOAc to 5%MeOH EtOAc to give the4-({[2-(2,4-Dimethoxy-benzylamino)-pyridine4-carbonyl]-amino}-methyl)-piperidine-1-carboxylicacid benzyl ester.

M.S. (M⁺+1) 519

Example 1724-{[(2-Amino-pyridine-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacid benzyl ester

4-({[2-(2,4-Dimethoxy-benzylamino)-pyridine-4-carbonyl]-amino}-methyl)-piperidine-1-carboxylicacid benzyl ester (EXAMPLE 171) (124 mg) in dichloromethane (5 mL) wastreated with trifluoroacetic acid (0.5 mL). After 30 min, the reactionmixture was partitioned between EtOAc and dilute sodium bicarbonatesolution. The organic layer was washed with brine, dried and the solventevaporated to give the crude product which was stirred with ether (3mL)and filtered to give the4-{[(2-amino-pyridine-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacid benzyl ester as a white solid.

M.S. (M⁺+1) 369

Example 1734-({[2-(2-Dimethylamino-ethylamino)-pyridine-4-carbonyl]-amino}-methyl)-piperidine-1-carboxylicacid benzyl ester

A mixture of4-{[(2-chloro-pyridine-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacid benzyl ester (EXAMPLE 65) (50 mg, 0.8 mmol) andN,N-dimethylethylenediamine (0.2 mL) were heated to 100 C for 18 hours,cooled to room temperature. The reaction mixture was then purified byreverse phase BPLC to give the4-({[2-(2-dimethylamino-ethylamino)-pyridine-4-carbonyl]-amino}-methyl)-piperidine-1-carboxylicacid benzyl ester as its trifluoroacetate salt.

M.S. (M⁺+1) 440

Example 174N-[1-(2-Phenyl-ethanesulfonyl)-piperidin-4-ylmethyl]-isonicotinamide

Step 1:

4-Aminomethyl-piperidine-1-carboxylic acid tert-butyl ester

To a mixture of 15 g of 4-aminomethylpiperidine in 250 mL of anhydroustetrahydrofuran cooled to −78° C. was added dropwise over 45 min asolution of 24 g of di-tert-butyl di-carbonate in 100 mL of anhydroustetrahydrofuran. After stirring for 1 h at −78° C., the mixture wasallowed to warm to rt and stirred overnight. The mixture wasconcentrated to near dryness and diluted with 200 mL of 10% aqueouscitric acid. The mixture was extracted with 3×100 mL of ether, then madebasic with sodium hydroxide pellets and extracted with 3×200 mL ofchloroform. The combined chloroform extracts were dried over magnesiumsulfate and concentrated to dryness under reduced pressure. Theresulting oil was homogeneous by TLC (development with 90:10 chloroformsaturated with ammonia: methanol).

¹H NMR (400 MHz, CDCl₃): 4.1 (br s, 2 H), 2.7 (br m, 2H), 2.6 (d, 2H),1.7 (m, 3H), 1.42 (s, 9H), 1.1 (m, 2H).

Step 2:

4-(Benzyloxycarbonylamino-methyl)-piperidine-1-carboxylic acidtert-butyl ester

To a solution of 21 g of 4-aminomethyl-piperidine-1-carboxylic acidtert-butyl ester in 100 mL of ethyl acetate cooled to 0° C. was added100 mL of saturated sodium carbonate and 17 g of benzyl chloroformate.The solution was stirred for 3 h, then separated. The organic layer wasdried over magnesium sulfate and concentrated under reduced pressure.Drying under vacuum gave the product as an oil:

¹H NMR (400 MHz, CDCl₃): 7.35 (m, 5H), 5.3 (d, 1H), 5.1 (s, 2H), 4.1 (brs, 2 H), 3.0 (br m, 2H), 2.6 (br m, 2H), 1.7 (m, 3H), 1.42 (s, 9H), 1.1(m, 2H).

Step 3:

Piperidin-4-ylmethyl-carbamic acid benzyl ester

A mixture of 35 g of4-(benzyloxycarbonylamino-methyl)-piperidine-1-carboxylic acidtert-butyl ester and 50 mL of 4N HCl in dioxane was stirred at rt for 3h, then diluted with 200 mL of ether and filtered. Thepiperidin-4-ylmethyl-carbamic acid benzyl ester hydrochloride salt wasobtained as a white fluffy solid. The free base was obtained bypartitioning the hydrochloride between 50 mL chloroform and 50 mLsaturated aqueous Na₂CO₃.

MS (m+1)=249;

¹H NMR (400 MHz, CDCl₃)): 7.35 (m, 5H), 5.15 (s, 2H), 4.9 (br s, 1 H),3.1 (m, 2H), 2.6 (m, 3H), 1.7 (m, 2H), 1.6 (m, 2H), 1.1 (m, 2H).

Step 4:

[1-(2-Phenyl-ethenesulfonyl)-piperidin-4-ylmethyl]-carbamic acid benzylester

A mixture of 2 g of piperidin-4-ylmethyl-carbamic acid benzyl esterhydrochloride, 25 mL of dichloromethane, 1.5 grams oftrans-2-styrenesulfonyl chloride, and 3 mL of N,N-diisopropylethylaminewas stirred at rt overnight, then diluted with 200 mL of chloroform, andwashed with 100 mL of saturated sodium carbonate. The chloroformextracts were dried over magnesium sulfate and concentrated. The[1-(2-phenyl-ethenesulfonyl)-piperidin-4-ylmethyl]-carbamic acid benzylester was obtained as a white solid.

MS (m+1)=415;

¹H NMR (400 MHz, CDCl₃) ): 7.5–7.2 (m, 10H), 6.65 (m, 1H), 5.15 (s, 2H),4.8 (br s, 1H), 3.8 (d, 2H), 3.1 (dd, 2H), 2.6 (dd, 2H), 1.8 (d, 2H),1.6 (m, 2H), 1.35 (m, 2H).

Step 5:

C-[1-(2-Phenyl-ethanesulfonyl)-piperidin-4-yl]-methylamine

A mixture of 2.5 g of[1-(2-phenyl-ethenesulfonyl)-piperidin-4-ylmethyl]-carbamic acid benzylester, 1 g of 20% palladium hydroxide on carbon, 200 mL of methanol and50 mL of tetrahydrofuran were shaken under 50 psi of hydrogen for 2 daysat rt. The catalyst was filtered off and washed with 250 mL of methanol.Concentration under reduced pressure gave theC-[1-(2-phenyl-ethanesulfonyl)-piperidin-4-yl]-methylamine as a whitesolid.

MS (m+1)=283;

¹H NMR (400 MHz, CDCl₃) ): 7.4–7.2 (m, 5H), 5.1 (s, 2H), 3.8 (d, 2H),3.1 (m, 4H), 2.7 (dd, 2H), 1.8 (d, 2H), 1.6 (m, 5H), 1.3 (m, 2H).

Step 6:

N-[1-(2-Phenyl-ethanesulfonyl)-piperidin-4-ylmethyl]-isonicotinamide

The N-[1-(2-Phenyl-ethanesulfonyl)-piperidin-4-ylmethyl]-isonicotinamidewas prepared fromC-[1-(2-phenyl-ethanesulfonyl)-piperidin-4-yl]-methylamine andisonicotinic acid as described above in EXAMPLE 1, Step 2.

MS (m+1)=388.

Example 175N-{1-[2-(4-Fluoro-phenyl)-ethanesulfonyl]-piperidin-4-ylmethyl}-4-hydroxy-benzamide

Step 1:

1-(2—Chloro-ethyl)-4-fluoro-benzene

A mixture of 7 g of 2-(4-fluoro-phenyl)-ethanol, 25 mL of chlorobenzene,42 mL of 37% HCl, and 0.9 g of Aliquat® 336 (tricaprylylmethyl ammoniumchloride) was heated to reflux for 3 days, cooled and extracted into3×100 mL of hexane. The combined extracts were dried over magnesiumsulfate and concentrated under reduced pressure. The resulting oil was acrude product of 1-(2-chloro-ethyl)-4-fluoro-benzene:

¹H NMR (400 MHz, CDCl₃): 7.3 (dd, 2H), 7.0 (dd, 2H), 3.7 (t, 2H), 3.05(t, 2H).

Step 2:

Thioacetic acid S-[2-(4-fluoro-phenyl)-ethyl] ester

A mixture of 2.4 g of 1-(2-chloro-ethyl)-4-fluoro-benzene, 30 mL of DMF,and 2.5 g of potassium thioacetate was stirred under nitrogen for 24 h.The mixture was diluted with 200 mL of water and extracted with 3×50 mLof dichloromethane. The combined organic layers were dried overmagnesium sulfate and concentrated under reduced pressure. Drying undervacuum gave the product as an oil:

¹H NMR (400 MHz, CDCl₃): 7.18 (dd, 2H), 6.98 (dd, 2H), 3.08 (t, 2H),2.81 (t, 2H), 2.32 (s, 3H).

Step 3:

2-(4-Fluoro-phenyl)-ethanesulfonyl chloride

A stream of chlorine gas was dispersed into a stirred, ice cold mixtureof 2.5 g of thioacetic acid S-[2-(4-fluoro-phenyl)-ethyl] ester, 30 mLof dichloromethane and 30 mL of water over 1 h. The mixture was dilutedwith 200 mL of dichloromethane, shaken and separated. The combinedorganic layers were dried over magnesium sulfate and concentrated underreduced pressure. Trituration with hexane gave a white solid:

¹H NMR (400 MHz, CDCl₃): 7.2 (dd, 2H), 7.0 (dd, 2H), 3.1 (dd, 2H), 3.3(dd, 2H), 2.32 (s, 3H).

Step 4:

4-(tert-Butoxycarbonylamino-methyl)-piperidine-1-carboxylic acid benzylester

To an ice cold, stirred solution of 21 g of4-aminomethyl-piperidine-1-carboxylic acid benzyl ester in 250 mL ofdichloromethane was added 18 g of di-tert-butyldicarbonate in 100 mL ofdichloromethane over 30 min. After stirring overnight, the mixture wasconcentrated to dryness. Trituration with hexane gave a white solid:

¹H NMR (400 MHz, CDCl₃): 7.4 (m, 5H), 5.15 (s, 2H), 4.6 (br s, 1H), 4.2(br s, 2H), 3.0 (br s, 2H), 2.8 ((m, 2H), 1.7 (m, 3H), 1.42 (s, 9H),1.15 (m, 2H).

Step 5:

Piperidin-4-ylmethyl-carbamic acid tert-butyl ester

A mixture of 28 g of4-(tert-butoxycarbonylamino-methyl)-piperidine-1-carboxylic acid benzylester, 1 g of 10% palladium on carbon, 100 mL of THF and 200 mL ofmethanol was stirred under an atmosphere of hydrogen for 2 days. Themixture was filtered concentrated under reduced pressure. Drying underreduced pressure gave a white solid:

¹H NMR (400 MHz, CDCl₃): 4.8 (br s, 1H), 3.05 (d, 2H), 2.9 (dd, 2H), 2.6(m, 3H), 1.6 (d, 2H), 1.5 (m, 1H), 1.4 (s, 9H), 1.05 (m, 2H).

Step 6:

{1-[2-(4-Fluoro-phenyl)-ethanesulfonyl]-piperidin-4-ylmethyl}-carbamicacid tert-butyl ester

To an ice cold, stirred solution of 0.2 g ofpiperidin-4-ylmethyl-carbamic acid tert-butyl ester and 0.2 mL ofN,N-diisopropylethyl amine in 20 mL of dichloromethane was added 0.3 gof 2-(4-fluoro-phenyl)-ethanesulfonyl chloride. After stirringovernight, the mixture was diluted with 50 mL of chloroform, washed with50 mL of saturated sodium carbonate, dried over magnesium sulfate andconcentrated to dryness under reduced pressure. Trituration with hexanegave a white solid:

¹H NMR (400 MHz, CDCl₃): 7.2 (m, 2H), 7.0 (dd, 2H), 4.6 (br m, 1H), 3.8(d, 2H), 3.1 (m, 3H), 3.0 (m, 2H), 2.7 (dd, 2H), 1.8 (d, 2H), 1.6 (br m,2H), 1.42 (s, 9H), 1.3 (m, 2H).

Step 7:

C-{1-[2-(4-Fluoro-phenyl)-ethanesulfonyl]-piperidin-4-yl}-methylamine

A mixture of 0.4 g of{1-[2-(4-fluoro-phenyl)-ethanesulfonyl]-piperidin-4-ylmethyl}-carbamicacid tert-butyl ester and 5 mL of 4N HCl in dioxane was stirred at rtfor 3 h, then diluted with 50 mL of chloroform, washed with 50 mL ofsaturated sodium carbonate, dried over magnesium sulfate andconcentrated to dryness under reduced pressure. The product was a whitesolid:

MS (m+1)=301;

¹H NMR (400 MHz, CDCl₃): 7.2 (m, 2H), 7.0 (dd, 2H), 3.92 (d, 2H), 3.1(s, 4H), 2.7 (dd, 2H), 2.6 (d, 2H), 1.8 (d, 2H), 1.5 (br m, 3H), 1.3 (m,2H).

Step 8:

N-{1-[2-(4-Fluoro-phenyl)-ethanesulfonyl]-piperidin-4-ylmethyl}-4-hydroxy-benzamide

N-{1-[2-(4-Fluoro-phenyl)-ethanesulfonyl]-piperidin-4-ylmethyl}-4-hydroxy-benzamidewas prepared fromC-{1-[2-(4-fluoro-phenyl)-ethanesulfonyl]-piperidin-4-yl}-methylamineand 4-hydroxybenzoic acid as described above in EXAMPLE 1, Step 2

MS (m+1)=421.

The following compounds were prepared as described in EXAMPLE 175, butreplacing the 4-fluorophenethyl alcohol with the appropriatelysubstituted phenethyl alcohol in Step 1 and using the appropriatecarboxylic acid in Step 8.

EX. Name Structure Analytical Data 176N-[1-(2-p-Tolyl-ethanesulfonyl)-piperidin-4-ylmethyl]-isonicotinamide

MS (m + 1) = 402.5. 177 3H-Benzoimidazole-5-carboxylic acid[1-(2-phenyl-ethane-sulfonyl)-piperidin-4-ylmethyl]-amide

MS (m + 1) = 427.5. 178 Pyrimidine-4-carboxylic acid[1-(2-phenyl-ethane-sulfonyl)-piperidin-4-ylmethyl]-amide

MS (m + 1) = 389. 179 2-Amino-pyrimidine-5-carboxylicacid[1-(2-phenyl-ethane-sulfonyl)-piperidin-4-ylmethyl]-amide

MS (m + 1) = 391 180 Pyrazine-2-carboxylic acid[1-(2-phenyl-ethane-sulfonyl)-piperidin-4-ylmethyl]-amide

MS (m + 1) = 389 181 3-Amino-pyrazine-2-carboxylic acid[1-(2-phenyl-ethane-sulfonyl)-piperidin-4-ylmethyl]-amide

MS (m + 1) = 404 182 Pyrimidine-5-carboxylic acid[1-(2-phenyl-ethane-sulfonyl)-piperidin-4-ylmethyl]-amide

MS (m + 1) = 389 183 Pyrimidine-4-carboxylic acid[1-(2-p-tolyl-ethane-sulfonyl)-piperidin-4-ylmethyl]-amide

MS (m + 1) = 389 184 9H-Purine-6-carboxylic acid[1-(2-phenyl-ethane-sulfonyl)-piperidin-4-ylmethyl]-amide

MS (m + 1) = 429 185N-{1-[2-(4-Chloro-phenyl)-ethane-sulfonyl]-piperidin-4-ylmethyl}-4-hydroxy-benzamide

MS (m + 1) = 437 186N-{1-[2-(2-Fluoro-phenyl)-ethane-sulfonyl]-piperidin-4-ylmethyl}-4-hydroxy-benzamide

MS (m + 1) = 421 1876-Hydroxy-N-[1-(2-phenyl-ethane-sulfonyl)-piperidin-4-ylmethyl]-nicotinamide

MS (m + 1) = 404 1884-Hydroxy-N-[1-(2-phenyl-ethane-sulfonyl)-piperidin-4-ylmethyl]-benzamide

MS (m + 1) = 403 189 Pyridazine-4-carboxylic acid[1-(2-phenyl-ethane-sulfonyl)-piperidin-4-ylmethyl]-amide

MS (m + 1) = 389

Example 190 (R,S)3-[(4-Hydroxy-benzoylamino)-methyl]-pyrrolidine-1-carboxylic acid benzylester

Step 1:

1-Benzyl-pyrrolidine-3-carboxylic acid amide

To a mixture of 4.4 g of 1-benzyl-pyrrolidine-3-carboxylic acid methylester (M. J. Kornet et al., J. Org. Chem., 33:3637–3639(1968)) and 3 gof formamide in 10 mL of anhydrous DMF heated to 100° C. was added asolution of sodium methoxide, from 0.33 g of sodium dissolved inmethanol, dropwise over 20 min. After stirring for 1 h at 100° C., themixture was allowed to cool to rt and added to 100 mL of isopropanol.The mixture was concentrated to dryness. The resulting residue wastriturated with 200 mL of chloroform, filtered and concentrated todryness under reduced pressure. The resulting oil was fairly homogeneousby TLC (development with 90:10 chloroform saturated with ammonia:methanol):

¹H NMR (400 MHz, CDCl₃): 7.1 (5H), 4.3 (br s, 2 H), 3.5 (d, 2H), 3.4 (m,1H), 2.6 (m, 2H), 2.5 (m, 1H), 2.25 (m, 1H), 1.9 (m, 1H).

Step 2:

3-Carbamoyl-pyrrolidine-1-carboxylic acid benzyl ester

A mixture of 4.5 g of 1-benzyl-pyrrolidine-3-carboxylic acid amide, 200mL of THF, 20 mL of methanol, and 1 g of 20% palladium hydroxide oncarbon was shaken under 50 psi of hydrogen for 12 h. The catalyst wasfiltered off and the filtrate concentrated under reduced pressure.Drying under vacuum gave 3 g of an oil. To a stirred solution of thecrude residue in 500 mL of chloroform was added 5.5 g ofN-(benzyloxycarbonyloxy)succinimide and 2.2 mL of triethylamine. Themixture was allowed to stir overnight and washed with 50 mL of saturatedsodium carbonate dried over magnesium sulfate and concentrated todryness. Purification by chromatography on silica gel, eluting with90:10 ethyl acetate: methanol, gave the product as a resin:

¹H NMR (400 MHz, CDCl₃): 7.35 (m, 5H), 5.6 (br m, 2H), 3.6 (m, 3H), 3.4(m, 1H), 2.9 (br m, 1H), 2.1 (m, 2H).

Step 3:

3-Aminomethyl-pyrrolidine-1-carboxylic acid benzyl ester

A mixture of 1 g of 3-carbamoyl-pyrrolidine-1-carboxylic acid benzylester and 24 mL of 1M borane-THF was stirred at room temperature for 24h, then quenched with 50 mL of 3N HCl. The mixture was concentratedunder reduced pressure, followed by being partitioned between 50 mLchloroform and 25 mL saturated aqueous sodium carbonate. Concentrationof the combined extracts after drying over magnesium sulfate gave theproduct as a resin:

¹H NMR (400 MHz, CDCl₃)): 7.35 (m, 5H), 5.15 (s, 2H), 3.7–4 (complex,4H), 2.7 (m, 1H), 2.4–2.0 (complex, 2H), 1.6 (m, 4H).

Step 4:

(R,S) 3-[(4-Hydroxy-benzoylamino)-methyl]-pyrrolidine-1-carboxylic acidbenzyl ester

(R,S) 3-[(4-Hydroxy-benzoylamino)-methyl]-pyrrolidine-1-carboxylic acidbenzyl ester was prepared from 3-aminomethyl-pyrrolidine-1-carboxylicacid benzyl ester and 4-hydroxybenzoic acid as described above inEXAMPLE 1, Step 2.

MS (m+1)=395.

Example 191 (R)3-[(4-Hydroxy-benzoylamino)-methyl]-pyrrolidine-1-carboxylic acid benzylester and (S)3-[(4-Hydroxy-benzoylamino)-methyl]-pyrrolidine-1-carboxylic acid benzylester

Resolution of (R,S)3-[(4-hydroxy-benzoylamino)-methyl]-pyrrolidine-1-carboxylic acid benzylester (EXAMPLE 190) was performed on a Chirapak® preparative chiral KPLCcolumn:

MS (m+1)=395.

Example 192 2-Amino-pyrimidine-5-carboxylic acid[1-(2-phenyl-ethanesulfonyl)-piperidin-4-ylmethyl]-amide

Step 1:

(5-{[1-(2-Phenyl-ethanesulfonyl)-piperidin-4-ylmethyl]carbamoyl}-pyrimidin-2-yl)-carbamicacid tert-butyl ester

(5-{[1-(2-Phenyl-ethanesulfonyl)-piperidin-4-ylmethyl]-carbamoyl}-pyrimidin-2-yl)-carbamicacid tert-butyl ester was prepared fromC-[1-(2-phenyl-ethanesulfonyl)-piperidin-4-yl]-methylamine and2-tert-butoxycarbonylamino-pyrimidine-5-carboxylic acid (prepared by BOCprotection of ethyl 2-amino-5-pyrimidine carboxylate [prepared asdescribed by P. Schenone, et al., J. Heterocyclic Chem.,27:295–305(1990)] using di-tert-butyl dicarbonate and4-dimethylaminopyridine in acetonitrile, followed by saponification withsodium hydroxide and neutralization with dilute aqueous HCl) asdescribed in EXAMPLE 1, Step 2:

MS (m+1)=504.

Step 2:

2-Amino-pyrimidine-5-carboxylic acid[1-(2-phenyl-ethanesulfonyl)-piperidin-4-ylmethyl]-amide

2-Amino-pyrimidine-5-carboxylic acid[1-(2-phenyl-ethanesulfonyl)-piperidin-4-ylmethyl]-amide was preparedfrom(5-{[1-(2-phenyl-ethanesulfonyl)-piperidin-4-ylmethyl]-carbamoyl}-pyrimidin-2-yl)-carbamicacid tert-butyl ester by stirring at rt for 3 h in 4N HCl in dioxane.The product was precipitated as the hydrochloride salt by dilution withether and filtration.

MS (m+1)=404.

Example 193 2-Amino-pyrimidine-5-carboxylic acid[1-(2-p-tolyl-ethanesulfonyl)-piperidin-4-ylmethyl]-amide

The title compound was prepared fromC-[1-(2-p-tolyl-ethanesulfonyl)-piperidin-4-yl]-methylamine and2-tert-butoxycarbonylamino-pyrimidine-5-carboxylic acid, followed bytreatment with 4N HCl in dioxane as described in EXAMPLE 192.

MS (m+1)=418.

The following compounds were prepared by coupling4-aminomethyl-piperidine-1-carboxylic acid benzyl ester (EXAMPLE 1,Step 1) with the appropriate acid as described in EXAMPLE 1, Step 2.

EX. Name Structure Analytical Data 1944-{[(3-Methyl-3H-imidazole-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacidbenzyl ester

MS (m + 1) = 357 1954-{[(3-Methyl-3H-imidazole-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacid 4-methyl-benzyl ester

MS (m + 1) = 371 1964-{[(9H-Purine-6-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacidbenzyl ester

MS (m + 1) = 395

Example 1973-Hydroxy-4-[(4-hydroxy-benzoylamino)-methyl]-piperidine-1-carboxylicacid benzyl ester

Step 1:

1-Benzyl-4-hydroxymethyl-piperidin-3-ol

Sodium borohydride (40 g) was added in portions to a stirred solution ofethyl N-benzyl-3-oxopiperidine-4-carboxylate hydrochloride in methanol(500 mL), over 2 h. Water (300 mL) was added slowly, the mixture stirredfor 15 min, and then the organics were evaporated. The resulting residuewas partitioned between DCM and water (×3), the combined organic layersdried over anhydrous sodium sulfate, and the solvent evaporated to givethe product as a cis trans mixture, used in the next step withoutfurther purification.

M.S. (M+1): 222.

Step 2:

3-Hydroxy-4-hydroxymethyl-piperidine-1-carboxylic acid benzyl ester

A solution of the 1-Benzyl-4-hydroxymethyl-piperidin-3-ol from Step 1above (13.5 g) in methanol (450 mL) was hydrogenated at 50 psi over 20%palladium hydroxide on charcoal (10 g) for 48 h in three batches. Thecombined reaction mixtures were filtered and the filtrate evaporated togive an oil. This oil was dissolved in water (100 mL) and dioxane (100mL), cooled to 5° C., and benzyl chloroformate (7.8 mL) was addedslowly. 1M NaOH was added to maintain pH of 10–11. After 30 min, thecooling bath was removed and reaction mixture stirred for 30 min. Thereaction mixture was concentrated to remove dioxane and the residueextracted with EtOAc (×3). The combined extracts were washed with brine,dried over anhydrous sodium sulfate and solvent evaporated to give amixture of cis and trans products. Purified by flash columnchromatography (80% EtOAc hexane to 5% MeOH EtOAc) gave the upper Rf cisisomer and the lower Rf trans isomer.

M.S. (M+1): 266.

Step 3:

Cis 3-Hydroxy-4-(toluene-4-sulfonyloxymethyl)-piperidine-1-carboxylicacid benzyl ester

A solution of the 3-Hydroxy-4-hydroxymethyl-piperidine-1-carboxylic acidbenzyl ester diol from Step 2 above (7.65 g) in chloroform (200 mL) wastreated with pyridine (2.6 mL) and 4-toluenesulfonyl chloride (6.05 g)and the reaction mixture heated to 60° C. for 18 h. Additional pyridine(0.85 mL) and 4-toluenesulfonyl chloride (2.0 g) were added to thecooled reaction and heating continued for a further 24 h. The reactionmixture was cooled to rt and washed with 10% aqueous citric acidsolution and water, dried over anhydrous sodium sulfate and the solventevaporated to give, after flash column chromatography, the Cis3-Hydroxy-4-(toluene-4-sulfonyloxymethyl)-piperidine-1-carboxylic acidbenzyl ester.

Step 4:

Cis 4-Aminomethyl-3-hydroxy-piperidine-1-carboxylic acid benzyl ester

A solution of the cis3-Hydroxy-4-(toluene-4-sulfonyloxymethyl)-piperidine-1-carboxylic acidbenzyl ester (6.80 g) from Step 3 above was dissolved in DME (50 mL) andtreated with sodium azide (3.16 g). The reaction mixture was then heatedto 50° C. for 48 h, cooled to rt, and partitioned between dilute aqueoussodium bicarbonate and EtOAc. The organic layer was washed with brine,dried over anhydrous sodium sulfate and solvent evaporated to give theazide, which was dissolved in THF (50 mL) and treated withtriphenylphosphine (14.07 g) and water (3.25 mL). The reaction mixturewas stirred for 18 h at rt, the volatiles evaporated, and the residuepurified by flash column chromatography (DCM to 80/20/2 DCM MeOH NH₄OH)to give the cis 4-Aminomethyl-3-hydroxy-piperidine-1-carboxylic acidbenzyl ester as an oil.

M.S. (M+1): 265.

Step 4:

3-Hydroxy-4-[(4-hydroxy-benzoylamino)-methyl]-piperidine-1-carboxylicacid benzyl ester

The3-Hydroxy-4-[(4-hydroxy-benzoylamino)-methyl]-piperidine-1-carboxylicacid benzyl ester was prepared from the cis4-Aminomethyl-3-hydroxy-piperidine-1-carboxylic acid benzyl ester (Step3 above) and 4-hydroxybenzoic acid as described in EXAMPLE 1, Step 2.

Example 198 3-[(4-Hydroxy-benzoylamino)-methyl]-piperidine-1-carboxylicacid benzyl ester

Step 1:

4-Hydroxy-N-pyridin-3-ylmethyl-benzamide

The 4-hydroxy-N-pyridin-3-ylmethyl-benzamide was prepared from3-(2-aminomethyl)pyridine and 4-hydroxybenzoic acid in as described inEXAMPLE 1, Step 2.

M.S. (M+1): 229.

Step 2:

4-Hydroxy-N-piperidin-3-ylmethyl-benzamide

To a solution of 4-hydroxy-N-pyridin-3-ylmethyl-benzamide (2.0 g, 0.0088mol) in acetic acid (135 mL) was added platinum oxide (200 mg) and themixture stirred under hydrogen for 3 h. The reaction was filtered andconcentrated in vacuo to give an oil.

M.S. (M+1): 235.

Step 3:

3-[(4-Hydroxy-benzoylamino)-methyl]-piperidine-1-carboxylic acid benzylester

To a mixture of 4-hydroxy-N-piperidin-3-ylmethyl-benzamide (135 mg,0.580 mmol) in tetrahydrofuran (5 mL) was added triethylamine (100 μL)and N-benzyloxycarbonyloxysuccinamide (144 mg, 0.580 mmol) and themixture stirred at rt for 3 h. The reaction was concentrated in vacuoand chromatographed on silica using 50–100% ethyl acetate/hexane to give3-[(4-hydroxy-benzoylamino)-methyl]-piperidine-1-carboxylic acid benzylester as a foam.

M.S. (M+1): 369.

Example 199 3-[(4-Hydroxy-benzoylamino)-methyl]-piperazine-1-carboxylicacid benzyl ester

Step 1:

1,4-Dibenzyl-2-chloromethyl-piperazine

The above compound was prepared according to the procedure described inBihan, G. et. al., J. Med. Chem., 42:1587–1603(1999).

Step 2:

2-Azidomethyl-1,4-dibenzyl-piperazine

To a solution of 1,4-dibenzyl-2-chloromethyl-piperazine (8.8 g, 0.028mol) in dimethylformamide (90 mL) under nitrogen was added sodium azide(5.5 g) and the reaction stirred at 50° C. for 18 h. The reaction wascooled and diluted with 10% aqueous sodium bicarbonate (100 mL) andwater (250 mL) and the mixture extracted with ethyl acetate (2×200 mL).The organic extracts were washed with 10% sodium bicarbonate, brine,dried over sodium sulfate and concentrated to an oil.

M.S. (M+1): 322.

Step 3:

C-(1,4-Dibenzyl-piperazin-2-yl)-methylamine

To a solution of 2azidomethyl-1,4-dibenzyl-piperazine (9.0 g, 0.028 mol)in TBFE (90 mL) and water (5 mL) was added triphenylphosphine (22.3 g,0.085 mol) and the mixture stirred for 18 h. The reaction wasconcentrated to an oil, dissolved in 1N hydrochloric acid (100 mL) andwashed with ethyl acetate (2×100 mL). The acidic aqueous layer wascooled to 0° C. and the pH adjusted to 8.5 with 3N sodium hydroxide. Themixture was extracted with ethyl acetate (2×100 mL) and extracts driedover sodium sulfate and concentrated to an oil.

M.S. (M+1): 296.

Step 4:

N-(1,4-Dibenzyl-piperazin-2-ylmethyl)-4-hydroxy-benzamide

The N-(1,4-Dibenzyl-piperazin-2-ylmethyl)-4-hydroxy-benzamide wasprepared from C-(1,4-Dibenzyl-piperazin-2-yl)-methylamine and4-hydroxybenzoic acid as described in EXAMPLE 1, Step 2.

M.S. (M+1): 416.

Step 5:

4-Hydroxy-N-piperazin-2-ylmethyl-benzamide

The 4-Hydroxy-N-piperazin-2-ylmethyl-benzamide was prepared according tothe procedure described in EXAMPLE 198, Step 2, using 10%Palladium/Carbon as catalyst in ethanol/12N HCl at 50° C. for 5 h.

M.S. (M+1): 236.

Step 6:

3-[(4-Hydroxy-benzoylamino)-methyl]-piperazine-1-carboxylic acid benzylester

The 3-[(4-Hydroxy-benzoylamino)-methyl]-piperazine-1-carboxylic acidbenzyl ester was prepared according to the procedure described inEXAMPLE 198, Step 3. Dilution of reaction with 10% aqueous sodiumbicarbonate and extraction with ethyl acetate followed by concentrationand purification by silica gel chromatography using 95/5/1 to 90/10/2(dichloromethane/methanol/NH₄OH) gave the3-[(4-Hydroxy-benzoylamino)-methyl]-piperazine-1-carboxylic acid benzylester as a solid.

M.S. (M+1): 370.

Example 2004-Hydroxy-N-[4-(3-phenyl-propionyl)-piperazin-2-ylmethyl]-benzamide

The title compound was prepared in a similar manner as described inEXAMPLE 1, Step 2, from 4-hydroxy-N-piperazin-2-ylmethyl-benzamide and4-hydroxybenzoic acid.

M.S. (M+1): 368.

Example 2014-Hydroxy-N-[4-(3-phenyl-propyl)-piperazin-2-ylmethyl]-benzamide

The title compound was prepared in a similar manner as described inEXAMPLE 148, Step 1, from 4-Hydroxy-N-piperazin-2-ylmethyl-benzamide andpropionaldehyde in dichlorethane as solvent.

M.S. (M+1): 354.

Example 202 2-[(4-Hydroxy-benzoylamino)-methyl]-morpholine-4-carboxylicacid benzyl ester

Step 1:

N-(4-Benzyl-morpholin-2-ylmethyl)-4-hydroxy-benzamide

The N-(4-Benzyl-morpholin-2-ylmethyl)-4-hydroxy-benzamide was preparedfrom C-(4-benzyl-morpholin-2-yl)-methylamine (S. Kato et al., J. MedChem., 33:1406(1990)) similarly to the procedure described in EXAMPLE 1,Step 2.

M.S. (M+1): 327

Step 2:

A solution of N-(4-benzyl-morpholin-2-ylmethyl)-4-hydroxy-benzamide(Step 1 above) (320 mg) was dissolved in ethanol (20 mL) andhydrogenated at 1 atm over 20% Pd(OH)₂/C (250 mg) for 18 h. The catalystwas removed by filtration, washed with ethanol, and the filtrateevaporated, to give a solid. A portion (21 mg) of this material wasdissolved in DMF (0.5 mL) and N-(benzyloxycarbonyloxy)succinimide (27mg) was added. The reaction mixture was stirred for 10 min, one drop ofwater was added and the solution was purified by preparative reversephase HPLC to give the2-[(4-Hydroxy-benzoylamino)-methyl]-morpholine4-carboxylic acid benzylester compound.

M.S. (M+1): 371

Example 2034-Hydroxy-N-[4-(3-phenyl-propyl)-morpholin-2-ylmethyl]-benzamide

A solution of N-(4-benzyl-morpholin-2-ylmethyl)-4-hydroxy-benzamide(EXAMPLE 202, Step 1) (55 mg) was dissolved in acetic acid (3 mL) andhydrogenated at 1 atm over 10% Pd/C (50 mg) for 18 h. The catalyst wasremoved by filtration, washed with acetic acid and the filtrateevaporated, to give an oil. A portion of this oil (21 mg) was dissolvedin methanol (1 mL) and treated with phenylpropionaldehyde (24 mg) andsodium cyanoborohydride (25 mg). The resulting reaction was stirred for15 min and the crude reaction mixture purified by preparative reversephase IPLC to give the4-Hydroxy-N-[4-(3-phenyl-propyl)-morpholin-2-ylmethyl]-benzamidecompound.

M.S. (M+1): 355

Acid Intermediates:

4-(1-Hydroxyethyl)benzoic acid

To a solution of methyl 4-(1-hydroxyethylbenzoate (150 mg, 0.83 mmol) inTBF (1 mL) was added 1M LiOH (1 mL). The reaction mixture was heated to60° C. and stirred for 1 h. After cooling, the reaction was acidifiedwith 1M HCl, and extracted with EtOAc twice. The organic layer was driedover Na₂SO₄, filtered and concentrated to give 4-(1-hydroxyethyl)benzoicacid as a white solid which was used without further purification.

4-(2-Hydroxyethyl)benzoic acid

To a solution of 0.5 g (3.40 mmol) of the nitrile and 20 mL ethanol wasadded 7 mL of 2N NaOH. The solution was heated at 98° C. for 18 h.,cooled, then evaporated. The remaining oil was dissolved into EtOAc andaqueous sodium bicarbonate. The organic layer was discarded. The aqueouslayer was acidified with 6N HCl, extracted into EtOAc, dried overNa₂SO₄, filtered and evaporated to yield the hydroxy acid as a whitesolid.

4-(1H-Imidazol-2-yl)benzoic acid

Ammonia gas was bubbled into a solution of 4-carboxybenzaldehyde (2.0 g,13.32 mmol) in water (15 mL) for 10 min. To clear soln was added glyoxal(2.9 mL, 19.98 mmol) in water (10 mL) dropwise over 15 min and thereaction mixture was stirred for 3 h. The solution was neutralized with6N HCl and filtered to give a white paste. Trituration with acetonefollowed by evaporation gave 4-(1H-imidazol-2-yl)benzoic acid as a whitesolid.

2-(Hydroxymethyl)-1,3-thiazole-4-carboxylic acid

Step 1:

Preparation of2-{[(2,2-dimethylpropanoyl)oxy]methyl}-1,3-thiazole-4-carboxylic acid

To a solution of bromopyruvic acid (0.37 g, 2.22 mmol) and2-(tert-butylcarbonyloxy)thioacetamide (0.41 g, 2.22 mmol) in ethanol(20 ml) was added 4 A molecular sieves (2 g). After stirring for 15 h,20 mL of dichloromethane was added. The mixture was stirred 5 min andfiltered to give the product as a yellow solid.

Step 2:

Preparation of 2-(hydroxymethyl)-1,3-thiazole-4-carboxylic acid

To the protected alcohol acid (0.36 g, 1.48 mmol) in MeOH (20 mL) andwater (6 mL) was added potassium carbonate (0.36 g, 0.26 mmol). Themixture was heated at reflux for 2 h. The methanol was removed in vacuoand the remaining aqueous reaction mixture was extracted with hot EtbAc(2×100 mL). The combined organic layers were dried over Na₂SO₄, filteredand evaporated to a yellow oil. Diethyl ether (20 mL) was added, and themixture was decanted and dried in vacuo to give the product as a brownpowder.

Example 204 4-Methylbenzyl4-({[4-(1-hydroxy-1-methylethyl)benzoyl]amino}methyl)piperidine-1-carboxylate

To a 0° C. solution of 4-methylbenzyl4-({[4-(methoxycarbonyl)benzoyl]-amino}methyl)-piperidine-1-carboxylate(EXAMPLE 538) (100 mg, 0.24 mmol) in THF (3 mL) was added methylmagnesiumbromide (0.39 mL, 1.18 mmol, 3.0M in Et₂O). The reactionmixture was warmed to rt, quenched with H₂O and extracted with EtOAc.The organic layer was dried over Na₂SO₄, filtered and concentrated. Theresidue was chromatographed on silica gel (gradient elution, 2:1hexane:EtOAc to EtOAc) to give 4-methylbenzyl4-({[4-(1-hydroxy-1-methylethyl)benzoyl]amino}methyl)piperidine-1-carboxylate.

(M+H)⁺=425.5

Example 205 4-Methylbenzyl4-({[3-(hydroxymethyl)benzoyl]amino}methyl)piperidine-1-carboxylate

To a solution of 4-methylbenzyl4-({[3-(methoxycarbonyl)benzoyl]amino}methyl)piperidine-1-carboxylate(EXAMPLE 540) (100 mg, 0.24 mmol) in MeOH (2 mL) was added sodiumborohydride (0.18 mg, 4.7 mmol). The solution was stirred at rt for 2 h,quenched with saturated NH₄Cl (aq) and extracted with EtOAc. The organiclayer was dried over NaSO₄, filtered and concentrated. The residue waschromatographed on silica gel (gradient elution, 2:1 hexane:EtOAc toEtOAc) to give 4-methylbenzyl4-({[3-(hydroxymethyl)benzoyl]amino}methyl)piperidine-1-carboxylate.

(M+H)⁺=397.5

Example 206 4-Methylbenzyl4-[({[3-(hydroxymethyl)-1H-pyrazol-5-yl]carbonyl}amino)methyl]piperidine-1-carboxylate

To5-({[(1-{[(4-methylbenzyl)oxy]carbonyl}piperidin-4-yl)methyl]amino}carbonyl)-1H-pyrazole-3-carboxylicacid (50 mg, 0.13 mmol) was added BH₃-THF solution (2.5 mL, 2.5 mmol,1.0M in THE). The solution was stirred at rt for 1 h, quenched with HCl(1M) and extracted with EtOAc. The organic layer was washed with H₂Odried over Na₂SO₄, filtered and concentrated. The residue waschromatographed on silica gel (gradient elution, EtOAc to 10%MeOH/EtOAc) to give 4-methylbenzyl4-[({[3-(hydroxymethyl)-1H-pyrazol-5-yl]carbonyl}amino)methyl]piperidine-1-carboxylate.

(M+H)⁺=387.5

Example 207 Benzyl4-({[(2-aminopyrinmidin-4-yl)carbonyl]amino}-methyl)piperidine-1-carboxylate

Step 1:

To P reparation of 1-bromo-2-(methylthio)pyrimidine-4-carboxylic acid

To a stirring solution of mucobromic acid (28.1 g, 109 mmol) and2-methyl-2-thiopseudourea sulfate (21.4 g, 109 mmol) in water (400 mL)under an argon atmosphere was added triethylamine (45.6 mL, 327 mmol)via a syringe pump (˜3 mL/h). After 18 h, conc. HCl (14 mL) was added tothe dark brown solution, stirred 30 min, then filtered. The resultingsolid was washed with water and dried to yield a brown solid. The solidwas dissolved in 400 mL water, and the pH was adjusted to ˜8 with solidsodium bicarbonate slowly to form a solution. To the solution, 10 g ofNorit decolorizing charcoal was added and the suspension was heated for1.25 h. at 100° C., cooled, then filtered through a pad of Celite. ThepH of the solution was adjusted to ˜0.3 with conc. HCl, allowed to stirin an ice bath for 30 min then filtered to yield 16.0 g of yellow solidafter drying in air.

Step 2:

Preparation of 2-(methylthio)pyrimidine-4-carboxylic acid

A solution of 5-bromo-2-(methylthio)pyrimidine-4-carboxylic acid (8.0 g,32.1 mmol) and potassium hydroxide (4.4 g, 32.1 mmol) in MeOH (175 mL)was transferred to a Parr hydrogenation jar. After purging the solutionwith nitrogen gas, of 5% Pd on barium sulfate (3.93 g) was added thenhydrogenated on Parr Hydrogenation Apparatus for 2 h at 40 psi. Themixture was filtered through a Celite pad. The resulting yellow solutionwas evaporated to ˜30 mL, then conc HCl was added to pH˜0.3, yielding ayellow solid carboxylic acid after filtration and air drying.

Step 3:

Preparation of 2-(methylsulfonyl)pyrimidine-4-carboxylic acid

To a solution of 2-(methylthio)pyrimidine-4-carboxylic acid (1.88 g(11.1 mmol) in THf (200 mL) was added Oxone (20.4 g, 33.1 mmol) in water(50 mL). The suspension was stirred for 24 h, then evaporated todryness. The resulting white paste was extracted 5× each 100 mL EtOAcand 5% MeOH in EtOAc. The combined extracts were dried over anhydrousMgSO₄, filtered and concentrated to give the sulfone as a white solid.

Step 4:

Preparation of benzyl4-[({[2-(methylsulfonyl)pyrimidin-4-yl]carbonyl}amino)methyl]piperidine-1-carboxylate

2-(Methylsulfonyl)pyrimidine-4-carboxylic acid was coupled to benzyl4-(aminomethyl)piperidine-1-carboxylate according to the procedure forEXAMPLE 1.

Step 5:

Preparation of benzyl4-({[(2-aminopyrimidin-4-yl)carbonyl]amino}-methyl)piperidine-1-carboxylate

Ammonia gas was bubbled through a solution of benzyl4-[({[2-(methylsulfonyl)pyrimidin4-yl]carbonyl}amino)methyl]piperidine-1-carboxylate(EXAMPLE 207, Step 4) (1.30 g, 3.01 mmol) in EtOAc (75 mL) for 10 min.The resulting solution was heated in a sealed pressure tube for 18 h. at65° C. The white suspension was then concentrated in vacuo. The mixturewas recrystallized using ˜20 mL EtOAc, and a minimal amount of MeOH,providing EXAMPLE 207 as a white solid. (M+H)⁺=370.4

Example 208 Benzyl4-[({[2-(methylamino)pyrimidin-4-yl]carbonyl}amino)methyl]piperidine-1-carboxylate

To a solution of benzyl4-[({[2-(methylsulfonyl)pyrimidin-4-yl]carbonyl}amino)methyl]piperidine-1-carboxylate(EXAMPLE 207, Step 4) (0.90 g, 3.01 mmol) in THF (75 mL) was added 40%aqueous methylamine (0.45 g). The resulting solution was heated for 18 hat 65° C., evaporated to dryness and purified by silica gelchromatography (gradient elution, 30 to 100% ethyl acetate in hexane) toprovide EXAMPLE 208 as a yellow gum. (M+H)⁺=384.3

Example 209 Benzyl4-[({[2-(dimethylamino)pyrimidin-4-yl]carbonyl}amino)methyl]piperidine-1-carboxylate

To a solution of benzyl4-[({[2-(methylsulfonyl)pyrimidin-4-yl]carbonyl}amino)methyl]piperidine-1-carboxylate(EXAMPLE 207, Step 4) (43 mg, 0.01 mmol) in THF (10 mL) was addeddimethylamine hydrochloride (23.6 mg, 0.3 mmol). The resulting solutionwas heated for 18 h at 80° C. and evaporated to dryness. Ethyl acetatewas added, and washed with sat'd aqueous sodium bicarbonate, water thenbrine. The organic layer was dried over Na₂SO₄, filtered andconcentrated. The resulting oil was purified by silica gelchromatography (gradient elution, 20 to 100% ethyl acetate in hexane) toprovide EXAMPLE 209 as a white foam. (M+H)⁺=398.3

Example 210 Benzyl4-({[(2-hydroxypyrimidin-4-yl)carbonyl]amino}methyl)piperidine-1-carboxylate

To a solution of benzyl4-[({[2-(methylsulfonyl)pyrimidin-4-yl]carbonyl}amino)methyl]piperidine-1-carboxylate(EXAMPLE 207, Step 4) (70 mg, 0.20 mmol) in THF (3 mL) was added NH₄OH(0.5 mL). The solution was stirred at rt for 2 h. The solution wasevaporated, water was added then extracted 2× with EtOAc, dried overNa₂SO₄, and evaporated to an oil. Silica gel column chromatography usinga 95:5:0.5 to 90:10:1 CH₂Cl₂:MeOH:NH₄OH gradient provided EXAMPLE 210 asa white solid. (M+H)⁺=371.4

Example 211 Benzyl4-({[(2-methoxypyrimidin-4-yl)carbonyl]amino}methyl)piperidine-1-carboxylate

A solution of benzyl4-[({[2-(methylsulfonyl)pyrimidin-4-yl]carbonyl}amino)methyl]piperidine-1-carboxylate(EXAMPLE 207, Step 4) (70 mg, 0.20 mmol) in MeOH (3 mL) was heated at60° C. for 18 h. The solution was evaporated, water was added thenextracted 2× with EtOAc, dried over Na₂SO₄, and evaporated to an oil.Silica gel column chromatography using a 95:5:0.5 to 90:10:1CH₂Cl₂:MeOH:NH₄OH gradient provided EXAMPLE 211 as a white solid.(M+H)⁺=385.4

Example 212 4-Methylbenzyl4-({[4-(2,2,2-trifluoro-1-hydroxyethyl)benzoyl]amino}methyl)piperidine-1-carboxylate

To a solution of 4-methylbenzyl4-({[4-(trifluoroacetyl)benzoyl]amino}methyl)piperidine-1-carboxylate(EXAMPLE 543) (250 mg, 0.54 mmol) in methanol (10 mL) was added sodiumborohydride (20.5 mg, 0.54 mmol). After 1 h., water (10 mL) was addedand the organics evaporated. The aqueous suspension was extracted 2×with EtOAc. The organics were dried over Na₂SO₄, filtered and evaporatedto a clear oil. Silica gel chromatography (gradient elution, 30 to 100%ethyl acetate in hexane), provided EXAMPLE 212 as a white foam.(M+H)⁺=465.4

Example 213 4-Methylbenzyl4-({[4-(aminomethyl)benzoyl]amino}methyl)piperidine-1-carboxylate

4-Methylbenzyl4-{[(4-{[(tert-butoxycarbonyl)amino]methyl}benzoyl)amino]methyl}piperidine-1-carboxylate(EXAMPLE 544) (200 mg, 0.40 mmol) was dissolved in EtOAc (10 mL), cooledto 0° C., and gaseous HCl was bubbled in for 10 min. After 30 min., themixture was evaporated to give a fine white powder of the hydrochloridesalt of EXAMPLE 213.

(M+H)⁺=396.4

Example 214 4-Methylbenzyl4-[({4-[(acetylamino)methyl]benzoyl}amino)methyl]piperidine-1-carboxylate

To a solution of EXAMPLE 213 (20 mg, 0.05 mmol), in CH₂Cl₂ (10 mL) wasadded triethylamine (14 μL, 0.10 mmol) and acetyl chloride (7.2 μL,0.092 mmol). After 5 min, water was added and the product was extractedinto CH₂Cl₂. Evaporation gave EXAMPLE 214 as a white solid. (M+H)⁺=438.3

Example 215 4-methylbenzyl4-{[(4-{[(methoxycarbonyl)amino]methyl}benzoyl)amino]methyl}piperidine-1-carboxylate

To a solution of EXAMPLE 213 (30 mg, 0.069mmol) in THF (5 mL) was addedtriethylamine (19.3 μL) and methylchloroformate (5.3 μL). The reactionmixture was stirred for 3 h then concentrated. Water and saturatedsodium bicarbonate was added and the aqueous layer was extracted withEtOAc. The organic layer was dried over Na₂SO₄, filtered andconcentrated to a white solid. Silica gel chromatography (75% ethylacetate in hexane to 95:5:0.5 ethyl acetate:MeOH:NH₄OH) provided EXAMPLE215 as a white solid. (M+H)⁺=454.4

Example 216 Benzyl4-fluoro-4-{[(4-hydroxybenzoyl)amino]methyl}piperidine-1-carboxylate

Step 1:

Preparation of tert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate

To a solution of tert-butyl 4-oxopiperidine-1-carboxylate (0.50 g, 2.51mmol) in THF/DME (2:1, 6 mL) at 60° C. was added trimethylsulfoxoniumiodide (0.58 g, 2.63 mmol) and sodium t-butoxide (0.25 g, 2.63 mmol).The reaction mixture was stirred at 60° C. for 30 min, cooled to rt andconcentrated. Water was added and the mixture was extract with EtOActwice. The combined organics were dried over Na₂SO₄, filtered andconcentrated. Purification on silica gel (3:1, hexanes:EtOAc) gavetert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate as a clear oil thatsolidified upon standing.

Step 2:

Preparation of benzyl 4-fluoro-4-(hydroxymethyl)piperidine-1-carboxylate

To a solution of tert-butyl 4-oxopiperidine-1-carboxylate (7.0 g, 32.8mmol) in CH₂Cl₂ (14 mL) at −10° C. was added HF-pyridine (11.6 mL, 82.1mmol) portionwise. The reaction mixture was stirred for 10 min at −10°C., warmed to rt. After stirring for 16 h, the reaction was carefullyquenched with aqueous NaCO₃, and extracted with CH₂Cl₂. The aquoueslayer was concentrated to a white paste that was suspended in CH₂Cl₂(100 mL). BOCOS (8.2 g, 32.8 mmol) was added and the mixture was stirredat RT for 3 h. The reaction mixture was partitioned between EtOAc andH₂O, the organic layer was dried over Na₂SO₄, filtered and concentrated.Purification on silica gel (10:1 to 1:1 hexanes:EtOAc) gave benzyl4-fluoro-4-(hydroxymethyl)piperidine-1-carboxylate as a clear oil.

Step 3:

Preparation of benzyl4-fluoro-4-{[(methylsulfonyl)oxy]methyl}piperidine-1-carboxylate

To a solution of benzyl4-fluoro-4-(hydroxymethyl)piperidine-1-carboxylate (1.0 g, 3.7 mmol) inCH₂Cl₂ (10 mL) at RT was added MsCl (0.29 mL, 3.7 mmol) and TEA (1.04mL, 7.5 mmol). The reaction mixture was stirred at RT for 5 min, andpartitioned between EtOAc and H₂O. The organic layer was dried overNa2SO4, filtered, concentrated and purified on silica gel (10:1 to 1:2hexanes:EtOAc) to give benzyl4-fluoro-4-{[(methylsulfonyl)oxy]methyl}piperidine-1-carboxylate.

Step 4:

Preparation of benzyl 4-(azidomethyl)-4-fluoropiperidine-1-carboxylate

To a solution of benzyl4-fluoro-4-{[(methylsulfonyl)oxy]methyl}piperidine-1-carboxylate (1.3 g,3.7 mmol) in DMF (10 mL) at RT was added NaN₃ (2.4 g, 37.0 mmol). Thereaction mixture was heated to 110° C. and stirred for 60 h, cooled andpartitioned between EtOAc and H₂O. The organic layer was dried overNa₂SO₄, filtered, concentrated and purified on silica gel (10:1 to 1:2hexanes:EtOAc) to give benzyl4-(azidomethyl)-4-fluoropiperidine-1-carboxylate.

Step 5:

Preparation of benzyl 4-(aminomethyl)-4-fluoropiperidine-1-carboxylate

To a solution of benzyl 4-(azidomethyl)-4-fluoropiperidine-1-carboxylate(1.5 g, 5.1 mmol) in THF (10 mL) at RT with added water (0.92 mL, 0.92mmol) and triphenylphosphine (4.3 g, 15.4 mmol). The reaction mixturewas stirred for 60 h, concentrated, dissolved in HCl (1M) and extractedwith Et₂O four times. The aqueous layer was basified to pH 11 andextracted with EtOAc twice. The organic layer was dried over Na₂SO₄,filtered and concentrated. The crude mixture was chromatographed onsilica gel (CH₂Cl₂ to 80:20:2 CH₂C12:MeOH:NH4OH) to give benzyl4-(aminomethyl)-4-fluoropiperidine-1-carboxylate.

Step 6:

Benzyl4-fluoro-4-{[(4-hydroxybenzoyl)amino]methyl}piperidine-1-carboxylate

4-Hydroxy benzoic acid was coupled to benzyl4-(aminomethyl)-4-fluoropiperidine-1-carboxylate according to theprocedure for EXAMPLE 1.

(M+H)⁺=387.3

Example 217 Benzyl4-({[(2-amino-1,3-thiazol-5-yl)carbonyl]amino}methyl)piperidine-1-carboxylate

Step 1:

Preparation of ethyl 2-amino-1,3-thiazole-5-carboxylate

To a mixture of B-ethoxyacrylic acid ethyl ester (2.0 g, 13.9 mmol) in1:1 dioxane/water (15 mL) at −10°0 C. was added NBS (2.72 g, 15.3 mmol).Thiourea (1.06 g, 13.9 mmol) was added and the mixture was heated to 80°C. and stirred for 1.5 h. The reaction mixture was cooled to 0° C. and 5mL of saturated ammonium hydroxide was added. A precipitate formed in 15min. The solid was filtered, washed with water and dried under vacuum,yielding a light orange solid.

Step 2:

Preparation of 2-[(tert-butoxycarbonyl)amino]-1,3-thiazole-5-carboxylicacid

To a solution of ethyl 2-amino-1,3-thiazole-5-carboxylate (1.88 g, 10.9mmol) in dioxane (100 mL) was added di-t-butyl dicarbonate (2.43 g, 12.0mmol) and 2N NaOH (16.4 mL, 32.8 mmol). The reaction mixture was stirred18 h. then concentrated in vacuo. The paste was partitioned betweenethyl acetate and water, the layers were separated, and the aqueousre-extracted twice with ethyl acetate. The combined organics were driedover anhydrous sodium sulfate and concentrated to give an oil. Theproduct was preabsorbed onto silica gel and column chromatography (10 to30% ethyl acetate in hexanes) afforded 3 g white solid. The solid wasadded to a solution of lithium hydroxide (0.5 g) in water/TBF (1:1, 100mL). The mixture was heated at 45° C. for 3d. The organics wereevaporated, and the product was partitioned between ethyl acetate andwater. The aqueous layer was then acidified to pH ˜4 with 6N HCl andfiltered to obtain an off white solid.

Step 3:

Preparation of benzyl4-{[({2-[(tert-butoxycarbonyl)amino]-1,3-thiazol-5-yl}carbonyl)amino]methyl}piperidine-1-carboxylate

2-[(tert-Butoxycarbonyl)amino]-1,3-thiazole-5-carboxylic acid wascoupled to benzyl 4-(aminomethyl)piperidine-1-carboxylate according tothe procedure for EXAMPLE 1.

Step 4:

Benzyl4-({[(2-amino-1,3-thiazol-5-yl)carbonyl]amino}methyl)piperidine-1-carboxylate

EXAMPLE 217 was prepared from benzyl4-{[({2-[(tert-butoxycarbonyl)amino]-1,3-thiazol-5-yl}carbonyl)amino]methyl}piperidine-1-carboxylateusing the procedure for EXAMPLE 174, Step 3.

(M+H)⁺=375.3

Example 2184-Hydroxy-N-{[1(4-methylbenzyl)piperidin-4-yl]methyl}benzamide

To a solution of 4-hydroxy-N-piperidin-4-ylmethyl-benzamide (EXAMPLE154, Step 1) (50 mg, 0.21 mmol) in MeOH (3 mL) was added4-methylbenzaldehyde (25 mg, 0.21 mmol) and sodium cyanoborohydride (40mg, 0.64 mmol). The reaction mixture was stirred at rt for 15 h,concentrated and purified by reverse-phase HPLC. (M+H)⁺=339.2

The following Examples were prepared utilizing appropriate proceduresfrom examples described above.

EX. Structure Name MS (M⁺ + 1) 219.

4-{[(3-Methyl-3H-imidazole-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacid 4-fluoro-benzyl ester 375.3 220.

4-[(4-Hydroxy-benzoylamino)-methyl]-piperidine-1-carboxylic acidbenzyl-methyl-amide 382.4 221.

N-[1-(4-Benzyloxy-[1,2,5]thiadiazol-3-yl)-piperidin-4-ylmethyl]-4-hydroxy-benzamide425.2 222.

1H-Pyrrole-3-carboxylic acid[1-(4-benzyloxy-[1,2,5]thiadiazol-3-yl)-piperidin-4-ylmethyl]-amide398.2 223.

4-{[(6-Hydroxy-pyrazine-2-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacid benzyl ester 371.3 224.

1H-Pyrazole-4-carboxylic acid[1-(3-p-tolyl-propionyl)-piperidin-4-ylmethyl]-amide 355.3 225.

1H-Pyrazole-4-carboxylic acid (1-benzyl-piperidin-4-ylmethyl)-amide299.3 226.

3-Hydroxy-4-[(4-hydroxy-benzoylamino)-methyl]-piperidine-1-carboxylicacid benzyl ester 385.3 227.

N-(1-Benzyl-piperidin-4-ylmethyl)-4-hydroxy-benzamide 325.3 228.

4-{[(1H-Pyrazole-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacidfuran-3-ylmethyl ester 333.2 229.

1H-Pyrrole-3-carboxylic acid[1-(3-phenyl-propionyl)-piperidin-4-ylmethyl]-amide 340.3 230.

4-Fluoro-4-{[(1-methyl-1H-pyrrole-2-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacid benzyl ester 374.3 231.

4-[(4-Hydroxy-benzoylamino)-methyl]-3-methoxy-piperidine-1-carboxylicacidbenzyl ester 399.3 232.

1H-Pyrrole-3-carboxylic acid[1-(3-phenyl-propyl)-piperidin-4-ylmethyl]-amide 326.3 233.

1H-Pyrrole-3-carboxylic acid[1-(2-phenyl-cyclopropanecarbonyl)-piperidin-4-ylmethyl]-amide 352.3234.

4-[(4-Hydroxy-benzoylamino)-methyl]-4-methyl-piperidine-1-carboxylicacidbenzyl ester 383.3 235.

4-[(4-Hydroxy-benzoylamino)-methyl]-4-phenyl-piperidine-1-carboxylicacidbenzyl ester 445.3 236.

4-{[(1H-Indole-5-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacidbenzyl ester 392.3 237.

1H-Indole-5-carboxylic acid[1-(2-phenyl-ethanesulfonyl)-piperidin-4-ylmethyl]-amide 426.3 238.

4-{[(2-Oxo-2,3-dihydro-benzooxazole-6-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacid benzyl ester 239.

4-{[(1H-Indole-6-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacidbenzyl ester 392.3 240.

1H-Indole-6-carboxylic acid[1-(2-phenyl-ethanesulfonyl)-piperidin-4-ylmethyl]-amide 426.3 241.

4-{[(1H-Pyrrole-3-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacidpyridin-4-ylmethyl ester 343.2 242.

4-{[(1H-Pyrrole-3-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacidthiophen-2-ylmethyl ester 348.2 243.

4-{[(1H-Pyrrole-3-carbonyl)-amino]-methyl}-piperidine-1-carboxylic acid1-methyl-1H-imidazol-4-yl methyl ester 346.2 244.

4-{[(1H-Pyrrole-3-carbonyl)-amino]-methyl}1-piperidine-1-carboxylicacidthiazol-4-ylmethyl ester 349.2 245.

4-{[(1-Methyl-1H-pyrrole-3-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacid 4-methyl-benzyl ester 370.3 246.

3-Hydroxy-4-[(4-hydraxy-benzoylamino)-methyl]-piperidine-1-carboxylicacid benzyl ester 385.3 247.

3-Hydroxy-4-[(4-hydroxy-benzoylamino)-methyl]-piperidine-1-carboxylicacid benzyl ester 385.3 248.

4-}[(1H-Pyrrole-3-carbonyl)-amino]-methyl}-piperidine-1-carboxylic acid4-fluoro-benzyl ester 360.2 249.

4-}[(1H-Pyrrole-3-carbonyl)-amino]-methyl}-piperidine-1-carboxylic acid4-iodo-benzyl ester 468.2 250.

4-[(4-Hydroxy-benzoylamino)-methyl]-piperidine-1-carboxylic acid4-iodo-benzyl ester 495.2 251.

4-Fluoro-4-{[(1H-pyrrole-3-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacid benzyl ester 360.2 252.

N-(1-Benzyl-4-hydroxy-piperidin-4-ylmethyl)-4-hydroxy-benzamide 341.2253.

4-Hydroxy-4-[(4-hydroxy-benzoylamino)-methyl]-piperidine-1-carboxylicacid benzyl ester 385.2 254.

4-{[(1H-Pyrrole-3-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacidthiazol-2-ylmethyl ester 349.2 255.

4-Amino-4-[(4-hydroxy-benzoylamino)-methyl]-piperidine-1-carboxylic acidbenzyl ester 384.3 256.

4-{[(1H-Pyrrole-3-carbonyl)-amino]-methyl}-piperidine-1-carboxylic acid2-methyl-thiophen-3-ylmethyl ester 362.2 257.

4-{[(1H-Pyrrole-3-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacid2,5-dichloro-thiophen-3-yl methyl ester 416.1 258.

4-Hydroxy-N-[4-hydroxy-1-(3-phenyl-propyl)-piperidin-4-ylmethyl]-benzamide369.2 259.

4-Hydroxy-N-(4-hydroxy-1-phenethyl-piperidin-4-ylmethyl)-benzamide 355.2260.

4-[(4-Benzyloxy-benzoylamino)-methyl]-3-hydroxy-piperidine-1-carboxylicacid benzyl ester 475.3 261.

1H-Pyrrole-3-carboxylic acid[1-(3-p-tolyl-propionyl)-piperidin-4-ylmethyl]-amide 354.3 262.

4{[(1H-Pyrrole-3-carbonyl)-amino]-methyl}-piperidine-1-carboxylic acid5-methyl-thiophen-2-ylmethyl ester 362.2 263.

3-Hydroxy-4-[(4-hydroxy-benzoylamino)-methyl]-piperidine-1-carboxylicacid benzyl ester 385.2 264.

4-{[(1H-Pyrrole-3-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacidcyclopropylmethyl ester 306.2 265.

4-{[(1H-Pyrrole-3-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacidcyclopentylmethyl ester 334.2 266.

4-{[(1H-Pyrrole-3-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacid2,5-dimethyl-thiophen-3-ylmethyl ester 376.1 267.

1H-Pyrrole-3-carboxylic acid[1-(4-chloro-benzyl)-piperidin-4-ylmethyl]-amide 332.2 268.

1H-Pyrrole-3-carboxylic acid[1-(5-methyl-thiophen-2-ylmethyl)-piperidin-4-ylmethyl]-amide 318.2 269.

1H-Pyrrole-3-carboxylic acid[1-(3-fluoro-benzyl)-piperidin-4-ylmethyl]-amide 316.2 270.

1H-Pyrrole-3-carboxylic acid[1-(2,5-dimethyl-thiophen-3-ylmethyl)-piperidin-4-ylmethyl]-amide 332.2271.

4-{[(1-Methyl-1H-pyrrole-3-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacid 4-fluoro-benzyl ester 374.2 272.

4-Hydroxy-N-[1-(2,4,6-trimethyl-benzenesulfonyl)-piperidin-4-ylmethyl]-benzamide416.2 273.

4-{[(1H-Pyrrole-3-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacidbicyclo[2.2.1]hept-2-ylmethyl ester 360.2 274.

4-{[(1H-Pyrrole-3-carbonyl)-amino]-methyl}-piperidine-1-carboxylic acid2-methyl-cyclopropylmethyl ester 320.2 275.

N-[1-(4-Fluoro-benzyl)-piperidin-4-ylmethyl]-4-hydroxy-benzamide 343.2276.

N-[1-(4-Chloro-benzyl)-piperidin-4-ylmethyl]-4-hydroxy-benzamide 359.1277.

4-Hydroxy-N-[1-(1H-pyrrol-2-ylmethyl)-piperidin-4-ylmethyl]-benzamide314.2 278.

4-Hydroxy-N-[1-(5-methyl-thiophen-2-ylmethyl)-piperidin-4-ylmethyl]-benzamide345.2 279.

4-Fluoro-4-{[(1H-pyrrole-3-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacid 4-methyl-benzyl ester 374.2 280.

4-Fluoro-4-{[(2H-pyrazole-3-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacid 4-methyl-benzyl ester 375.2 281.

4-Fluoro-4-{[(1H-pyrazole-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacid 4-methyl-benzyl ester 375.2 282.

4-[(4-Hydroxy-benzoylamino)-methyl]-piperidine-1-carboxylic acid5-methyl-thiophen-2-ylmethyl ester 411.2 283.

4-Fluoro-4-[(4-hydroxy-benzoylamino)-methyl]-piperidine-1-carboxylicacid 4-methyl-benzyl ester 401.2 284.

4-Fluoro-4-[(4-hydroxy-benzoylamino)-methyl]-piperidine-1-carboxylicacid 4-chloro-benzyl ester 421.2 285.

4-{[(1H-Pyrazole-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylic acid5-methyl-thiophen-2-ylmethyl ester 363.1 286.

4-Hydroxy-N-[3-hydroxy-1-(3-phenyl-propyl)-piperidin-4-ylmethyl]-benzamide369.2 287.

4-Hydroxy-N-[3-hydroxy-1-(4-methyl-benzyl)-piperidin-4-ylmethyl]-benzamide355.2 288.

4-Hydroxy-N-[3-hydroxy-1-(5-methyl-thiophen-2-ylmethyl)-piperidin-4-ylmethyl]-benzamide361.1 289.

4-Hydroxy-N-[1-(2-p-tolyloxy-acetyl)-piperidin-4-ylmethyl]-benzamide383.2 290.

4-{[(2-Amino-pyridine-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacid 4-methyl-benzyl ester 383.2 291.

N-{1-[2-(4-Chloro-phenoxy)-acetyl]-piperidin-4-ylmethyl}-4-hydroxy-benzamide403.2 292.

N-{1-[2-(4-Fluoro-phenoxy)-acetyl]-piperidin-4-ylmethyl}-4-hydroxy-benzamide387.3 293.

4-{[(2-Methylamino-pyridine-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacid 4-methyl-benzyl ester 397.2 294.

4-{[(2-Dimethylamino-pyridine-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacid 4-methyl-benzyl ester 411.3 295.

4-{[(1H-Pyrrole-3-carbonyl)-aminol]-methyl}-piperidine-1-carboxylic acid4-chloro-benzyl ester 376.3 296.

4-{[(2-Benzylamino-pyridine-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacid 4-methyl-benzy ester 473.3 297.

4-{[(2-Pentylamino-pyridine-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacid 4-methyl-benzyl ester 453.4 298.

4-({[2-(2-Fluoro-benzylamino)-pyridine-4-carbonyl]-amino}-methyl)-piperidine-1-carboxylicacid 4-methyl-benzyl ester 491.3 299.

4-({[2-(3-Fluoro-benzylamino)-pyridine-4-carbonyl]-amino}-methyl)-piperidine-1-carboxylicacid 4-methyl-benzyl ester 491.3 300.

4-({[2-(4-Fluoro-benzylamino)-pyridine-4-carbonyl]-amino}-methyl)-piperidine-1-carboxylicacid 4-methyl-benzyl ester 491.3 301.

4-Fluoro-4-{[(1H-pyrrole-3-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacid 4-fluoro-benzyl ester 378.2 302.

4-{[(2-Propylamino-pyridine-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacid 4-methyl-benzyl ester 425.3 303.

4-{[(2-Butylamino-pyridine-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacid 4-methyl-benzyl ester 439.3 304.

4-{[(2-Isobutylamino-pyridine-4-carbonyl)-aminol]-methyl}-piperidine-1-carboxylicacid 4-methyl-benzyl ester 439.3 305.

4-{[(2-Cyclobutylamino-pyridine-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacid 4-methyl-benzyl ester 437.3 306.

4-{[(2-Cyclopentylamino-pyridine-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacid 4-methyl-benzyl ester 451.3 307.

4-{[(2-Cyclohexylamino-pyridine-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacid 4-methyl-benzyl ester 465.3 308.

4-({[2-(Cyclohexyl-methyl-amino)-pyridine-4-carbonyl]-amino}-methyl)-piperidine-1-carboxylicacid 4-methyl-benzyl ester 479.3 309.

4-({[2-(1-Ethyl-propylamino)-pyridine-4-carbonyl]-amino}-methyl)-piperidine-1-carboxylicacid 4-methyl-benzyl ester 453.3 310.

4-({[2-(2-Methoxy-1-methyl-ethylamino)-pyridine-4-carbonyl]-amino}-methyl)-piperidine-1-carboxylicacid 4-methyl-benzyl ester 455.3 311.

4-{[(2-Pyrrolidin-1-yl-pyridine-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacid 4-methyl-benzyl ester 437.3 312.

4-{[(2-Azepan-1-yl-pyridine-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacid 4-methyl-benzyl ester 465.3 313.

4-(({2-[(Thiophen-2-ylmethyl)-amino]-pyridine-4-carbonyl}-amino)-methyl]-piperidine-1-carboxylicacid 4-methyl-benzyl ester 479.2 314.

4-({[2-(2-Methyl-benzylamino)-pyridine-4-carbonyl]-amino}-methyl)-piperidine-1-carboxylicacid 4-methyl-benzyl ester 487.3 315.

4-({[2-(3-Methyl-benzylamino)-pyridine-4-carbonyl]-amino}-methyl)-piperidine-1-carboxylicacid 4-methyl-benzyl ester 487.3 316.

4-({[2-(4-Methyl-benzylamino)-pyridine-4-carbonyl]-amino}-methyl)-piperidine-1-carboxylicacid 4-methyl-benzyl ester 487.3 317.

4-({[2-(2-Chloro-benzylamino)-pyridine-4-carbonyl]-amino}-methyl)-piperidine-1-carboxylicacid 4-methyl-benzyl ester 507.3 318.

4-({[2-(3-Chloro-benzylamino)-pyridine-4-carbonyl]-amino}-methyl)-piperidine-1-carboxylicacid 4-methyl-benzyl ester 507.3 319.

4-({[2-(4-Chloro-benzylamino)-pyridine-4-carbonyl]-amino}-methyl)-piperidine-1-carboxylicacid 4-methyl-benzyl ester 507.3 320.

4-{[(2-Phenethylamino-pyridine-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacid 4-methyl-benzyl ester 487.3 321.

4-Hydroxy-N-[1-(2-phenyl-cyclopropanecarbonyl)-piperidin-4-ylmethyl]-benzamide379.3 322.

4-Hydroxy-N-[1-(2-phenyl-cyclopropanecarbonyl)-piperidin-4-ylmethyl]-benzamide379.3 323.

4-Hydroxy-N-{1-[2-(naphthalen-2-yloxy)-acetyl]-piperidin-4-ylmethyl}-benzamide419.4 324.

N-{1-[2-(2-Chloro-phenoxy)-acetyl]-piperidin-4-ylmethyl}-4-hydroxy-benzamide403.3 325.

4-Hydroxy-N-[1-(2-phenoxy-acetyl)-piperidin-4-ylmethyl]-benzamide 369.4326.

4-Hydroxy-N-[1-(2-phenoxy-propionyl)-piperidin-4-ylmethyl]-benzamide383.4 327.

4-Hydroxy-N-[1-(2-phenylsulfanyl-acetyl)-piperidin-4-ylmethyl]-benzamide385.3 328.

4-[(3-Fluoro-4-hydroxy-benzoylamino)-methyl]-piperidine-1-carboxylicacid 4-fluoro-benzyl ester 405.3 329.

4-{[(Pyrimidine-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylic acid4-methyl-benzyl ester 369.4 330.

4-[(2,3,5,6-Tetrafluoro-4-hydroxy-benzoylamino)-methyl]-piperidine-1-carboxylicacid benzyl ester 441.3 331.

4-{[(Pyrimidine-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylic acid4-fluoro-benzyl ester 373.4 332.

4-{[(2-Cyano-pyridine-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacid benzyl ester 379.4 333.

4-[(4-Amino-benzoylamino)-methyl]-piperidine-1-carboxylic acid4-fluoro-benzyl ester 386.4 334.

4-{[(Thiazole-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylic acid4-fluoro-benzyl ester 378.4 335.

4-{[([1,2,5]Thiadiazole-3-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacid 4-fluoro-benzyl ester 379.4 336.

4-[(3-Acetyl-4-hydroxy-benzoylamino)-methyl]-piperidine-1-carboxylicacidbenzyl ester 411.4 337.

4-{[(3-Amino-6-chloro-pyridazine-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacid benzyl ester 404.4 338.

4-{[(3-Chloro-6-hydroxy-pyridazine-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacid benzyl ester 405.3 339.

4-{[(3-Hydroxy-pyridine-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacid benzyl ester 370.4 340.

4-{[(2-Fluoro-pyridine-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacid 4-methyl-benzyl ester 386.4 341.

4-{[(6-Methyl-2-oxo-1,2-dihydro-pyridine-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacid benzyl ester 384.4 342.

4-{[(2-Benzylamino-pyrimidine-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacid benzyl ester 460.4 343.

4-{[(2-Chloro-6-methylamino-pyridine-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacid benzyl ester 417.4 344.

4-({[2-Chloro-6-(2,4-dimethoxy-benzylamino)-pyridine-4-carbonyl]-amino}-methyl)-piperidine-1-carboxylicacid benzyl ester 553.5 345.

4-{[(2-Amino-6-chloro-pyridine-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacid benzyl ester 403.4 346.

4-[(3,5-Difluoro-4-hydroxy-benzoylamino)-methyl]-piperidine-1-carboxylicacid benzyl ester 405.4 347.

4-{[(4-Amino-2-hydroxy-pyrimidine-5-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacid benzyl ester 386.4 348.

4-[(4-Carboxy-benzoylamino)-methyl]-piperidine-1-carboxylic acid4-methyl-benzyl ester 411.4 349.

4-[2,5-Difluoro-4-hydroxy-benzoylamino)-methyl]-piperidine-1-carboxylicacid benzyl ester 405.4 350.

4-{[(Thiazole-4-carbonyl)-amino]-methyl}-piperidine-1-calboxylic acid4-iodo-benzyl ester 486.3 351.

Pyrimidine-4-carboxylic acid[1-(2-phenyl-cyclopropanecarbonyl)-piperidin-4-ylmethyl]-amide 365.4352.

Thiazole-4-carboxylic acid[1-(2-phenyl-cyclopropanecarbonyl)-piperidin-4-ylmethyl]-amide 370.4353.

4-{[(5-Hydroxy-pyrimidine-2-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacid benzyl ester 371.4 354.

4-[(4-Acetyl-benzoylamino)-methyl]-piperidine-1-carboxylic acid4-methyl-benzyl ester 409.3 355.

2-Fluoro-N-[1-(2-phenyl-cyclopropanecarbonyl)-piperidin-4-ylmethyl]-isonicotinamide382.4 356.

Pyrimidine-4-carboxylic acid[1-(2-phenyl-cyclopropanecarbonyl)-piperidin-4-ylmethyl]-amide 365.4357.

4-{[(2-Oxo-2,3-dihydro-1H-indole-5-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacid benzyl ester 408.3 358.

Thiazole-4-carboxylic acid[1-(2-phenyl-cyclopropanecarbonyl)-piperidin-4-ylmethyl]-amide 370.3359.

4-{[(2-Oxo-1,2,3,4-tetrahydro-quinoline-6-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacid benzylester 422.4 360.

4-{[(5-Amino-2-methyl-pyrimidine-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacid benzyl ester 384.4 361.

4-{[4-(1-Hydroxyimino-ethyl)-benzoylamino]-methyl}-piperidine-1-carboxylicacid 4-methyl-benzyl ester 424.3 362.

4-Cyano-N-[1-(2-phenyl-cyclopropanecarbonyl)-piperidin-4-ylmethyl]-benzamide388.3 363.

4-{[(2-Oxo-1,2-dihydro-quinoline-6-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacid benzyl ester 420.3 364.

4-[(4-Formyl-benzoylamino)-methyl]-piperidine-1-carboxylic acid4-methyl-benzyl ester 395.3 365.

Thiazole-4-carboxylic acid{1-[2-(2-fluoro-phenyl)-cyclopropanecarbonyl]-piperidin-4-ylmethyl}-amide388.2 366.

Thiazole-4-carboxylic acid{1-[2-(2,6-difluoro-phenyl)-cyclopropanecarbonyl]-piperidin-4-ylmethyl}-amide406.2 367.

2-Fluoro-N-{1-[2-(2-fluoro-phenyl)-cyclopropanecarbonyl]-piperidin-4-ylmethyl}-isonicotinamide400.3 368.

N-{1-[2-(2,6-Difluoro-phenyl)-cyclopropanecarbonyl]-piperidin-4-ylmethyl}-2-fluoro-isonicotinamide418.3 369.

4-{[(2-Methanesulfonyl-pyrimidine-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacid 4-methyl-benzyl ester 448.2 370.

4-{[(2-Amino-pyrimidine-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacid 4-methyl-benzyl ester 384.3 371.

2-Methanesulfonyl-pyrimidine-4-carboxylic acid[1-(2-phenyl-cyclopropanecarbonyl)-piperidin-4-ylmethyl]-amide 443.3372.

2-Amino-pyrimidine-4-carboxylicacid[1-(2-phenyl-cyclopropanecarbonyl)-piperidin-4-ylmethyl]-amide 380.2373.

4-{[(2-Ethoxy-thiazole-5-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacid benzyl ester 404.2 374.

4-{[(6-Chloro-pyridine-2-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacid benzyl ester 388.2 375.

4-{[(2-Methylamino-pyrimidine-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacid 4-methyl-benzyl ester 398.3 376.

4-{[(6-Amino-pyridine-2-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacid benzyl ester 369.2 377.

3-[(4-Hydroxy-benzoylamino)-methyl]-piperidine-1-carboxylic acid benzylester 369.2 378.

3-[(4-Hydroxy-benzoylamino)-methyl]-piperidine-1-carboxylic acid4-methyl-benzyl ester 383.3 379.

3-[(4-Hydroxy-benzoylamino)-methyl]-piperidine-1-carboxylic acid4-fluoro-benzyl ester 387.2 380.

4-Hydroxy-N-[1-(3-phenyl-propyl)-piperidin-3-ylmethyl]-benzamide 353.3381.

4-Hydroxy-N-(1-phenethyl-piperidin-3-ylmethyl)-benzamide 339.3 382.

3-[(4-Hydroxy-benzoylamino)-methyl]-piperidine-1-carboxylic acid benzylester 369.3 383.

3-[(4-Hydroxy-benzoylamino)-methyl]-piperidine-1-carboxylic acid benzylester 369.3 384.

4-Hydroxy-N-[3-hydroxy-1-(3-phenyl-propyl)-piperidin-3-ylmethyl]-benzamide369.3 385.

4-Hydroxy-N-(3-hydroxy-1-phenethyl-piperidin-3-ylmethyl)-benzamide 355.2386.

3-Hydroxy-3-[(4-hydroxy-benzoylamino)-methyl]-piperidine-1-carboxylicacid benzyl ester 385.2 387.

3-{[(1H-Pyrrole-3-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacidbenzyl ester 342.7 388.

3-{[(2H-Pyrazole-3-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacidbenzyl ester 343.2 389.

3-{[(1H-Pyrazole-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacidbenzyl ester 343.2 390.

3-{-(1H-Pyrro1e-3-carbonyl)-amino]-methyl}-piperidine-1-carboxylic acid4-methyl-benzyl ester 356.2 391.

3-{[(1H-Pyrazole-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylic acid4-methyl-benzyl ester 357.2 392.

3-{[(2H-Pyrazole-3-carbonyl)-amino]-methyl}-piperidine-1-carboxylic acid4-methyl-benzyl ester 357.2 393.

3-[(4-Hydroxy-benzoylamino)-methyl]-piperazine-1-carboxylic acid benzylester 370.2 394.

3-[(4-Hydroxy-benzoylamino)-methyl]-4-methyl-piperazine-1-carboxylicacidbenzyl ester 384.3 395.

4-Hydroxy-N-[4-(3-phenyl-propyl)-piperazin-2-ylmethyl]-benzamide 354.2396.

4-Hydroxy-N-(4-phenethyl-piperazin-2-ylmethyl)-benzamide 340.3 397.

4-Hydroxy-N-[4-(3-phenyl-propionyl)-piperazin-2-ylmethyl]-benzamide368.3 398.

3-[(4-Hydroxy-benzoylamino)-methyl]-piperazine-1-carboxylic acid benzylester 370.2 399.

3-[(4-Hydroxy-benzoylamino)-methyl]-piperazine-1-carboxylic acid benzylester 370.2 400.

3-[(4-Hydroxy-benzoylamino)-methyl]-piperazine-1-carboxylic acid4-fluoro-benzyl ester 388.2 401.

3-[(4-Hydroxy-benzoylamino)-methyl]-piperazine-1-carboxylic acid4-methyl-benzyl ester 384.2 402.

3-{[(2-Oxo-2,3-dihydro-benzooxazole-6-carbonyl)-amino]-methyl}-piperazine-1-carboxylicacid benzyl ester 411.2 403.

4-Hydroxy-N-(4-naphthalen-1-ylmethyl-piperazin-2-ylmethyl)-benzamide368.4 404.

4-Hydroxy-N-(4-naphthalen-2-ylmethyl-piperazin-2-ylmethyl)-benzamide354.2 405.

3-[(4-Hydroxy-benzoylamino)-methyl]-pyrrolidine-1-carboxylic acid benzylester 376.3 406.

3-[(4-Hydroxy-benzoylamino)-methyl]-pyrrolidine-1-carboxylic acid benzylester 376.3 407.

3-[(4-Hydroxy-benzoylamino)-methyl]-pyrrolidine-1-carboxylic acid benzylester 355.3 408.

3-[(4-Hydroxy-benzoylamino)-methyl]-pyrrolidine-1-carboxylic acid4-methyl-benzyl ester 369.3 409.

3-[(4-Hydroxy-benzoylamino)-methyl]-pyrrolidine-1-carboxylic acid4-fluoro-benzyl ester 373.3 410.

N-(1-Benzyl-pyrrolidin-3-ylmethyl)-4-hydroxy-benzamide 311.4 411.

2-[(4-Hydroxy-benzoylamino)-methyl]-morpholine-4-carboxylic acid benzylester 371.2 412.

2-[(4-Hydroxy-benzoylamino)-methyl]-morpholine-4-carboxylic acid4-methyl-benzyl ester 385.7 413.

4-Hydroxy-N-[-(3-phenyl-propyl)-morpholin-2-ylmethyl]-benzamide 355.2414.

2-[(4-Hydroxy-benzoylamino)-methyl]-morpholine-4-carboxylic acid4-chloro-benzyl ester 405.1 415.

2-[(4-Hydroxy-benzoylamino)-methyl]-morpholine-4-carboxylic acid4-fluoro-benzyl ester 389.1 416.

4-Hydroxy-N-(4-phenethyl-morpholin-2-ylmethyl)-benzamide 341.1 417.

4-Hydroxy-N-(4-phenylacetyl-morpholin-2-ylmethyl)-benzamide 355.2 418.

4-Hydroxy-N-[4-(3-phenyl-propionyl)-morpholin-2-ylmethyl]-benzamide369.2 419.

2-[(4-Hydroxy-benzoylamino)-methyl]-morpholine-4-carboxylic acid4-fluoro-benzyl ester 389.3 420.

2-[(4-Hydroxy-benzoylamino)-methyl]-morpholine-4-carboxylic acid4-chloro-benzyl ester 405.1 421.

2-[(4-Hydroxy-benzoylamino)-methyl]-morpholine-4-carboxylic acid benzylester 371.1 422.

4-Hydroxy-N-[4-(3-phenyl-propionyl)-morpholin-2-ylmethyl]-benzamide369.2 423.

4-Hydroxy-N-(4-phenethyl-morpholin-ylmethyl)-benzamide 341.2 424.

2-{[(Pyridine-4-carbonyl)-amino]-methyl}-morpholine-4-carboxylicacidbenzyl ester 56.2 425.

2-[(3-Fluoro-4-hydroxy-benzoylamino)-methyl]-morpholine-4-carboxylicacid benzyl ester 389.1 426.

2-[(2-Fluoro-4-hydroxy-benzoylamino)-methyl]-morpholine-4-carboxylicacid benzyl ester 389.1 427.

2-[(4-Hydroxy-3-methyl-benzoylamino)-methyl]-morpholine-4-carboxylicacid benzyl ester 385.2 428.

2-{[(3-Amino-pyridine-4-carbonyl)-amino]-methyl}-morpholine-4-carboxylicacid benzyl ester 371.1 429.

2-{[(1H-Pyrazole-4-carbonyl)-amino]-methyl}-morpholine-4-carboxylicacidbenzyl ester 345.2 430.

2-{[(6-Hydroxy-pyridine-3-carbonyl)-amino]-methyl}-morpholine-4-carboxylicacid benzyl ester 372.2 431.

2-{[(2-Oxo-2,3-dihydro-benzooxazole-6-carbonyl)-amino]-methyl}-morpholine-4-carboxylicacid benzyl ester 412.1 432.

2-[(4-Cyano-benzoylamino)-methyl]-morpholine-4-carboxylic acid benzylester 380.2 433.

2-[(4-Benzoyloxy-benzoylamino)-methyl]-morpholine-4-carboxylicacidbenzyl ester 475.2 434.

2-[(4-Methanesulfonylamino-benzoylamino)-methyl]-morpholine-4-carboxylicacid benzyl ester 448.1 435.

3-Fluoro-4-hydroxy-N-(4-phenethyl-morpholin-2-ylmethyl)-benzamide 359.2436.

2-Fluoro-4-hydroxy-N-(4-phenethyl-morpholin-2-ylmethyl)-benzamide 359.1437.

4-Hydroxy-3-methyl-N-(4-phenethyl-morpholin-2-ylmethyl)-benzamide 355.2438.

6-Hydroxy-N-(4-phenethyl-morpholin-2-ylmethyl)-nicotinamide 342.2 439.

2-Oxo-2,3-dihydro-benzooxazole-6-carboxylic acid(4-phenethyl-morpholin-2-ylmethyl)-amide 382.1 440.

4-Cyano-N-(4-phenethyl-morpholin-2-ylmethyl)-benzamide 350.2 441.

Benzoic acid 4-[(4-phenethyl-morpholin-2-ylmethyl)-carbamoyl]-phenylester 445.2 442.

4-Methanesulfonylamino-N-(4-phenethyl-morpholin-2-ylmethyl)-benzamide418.1 443.

1H-Pyrazole-4-carboxylic acid (4-phenethyl-morpholin-2-ylmethyl)-amide341.2 444.

4-Hydroxy-N-[5-oxo-4-(3-phenyl-propyl)-morpholin-2-ylmethyl]-benzamide369.7 445.

4-Hydroxy-N-(5-oxo-4-phenethyl-morpholin-2-ylmethyl)-benzamide 355.6446.

N-{4-[2-(4-Fluoro-phenyl)-ethyl]-morpholin-2-ylmethyl}-4-hydroxy-benzamide359.3 447.

2-{[(2-Oxo-2,3-dihydro-benzooxazole-6-carbonyl)-amino]-methyl}-morpholine-4-carboxylicacid benzylester 412.3 448.

2-[(4-Methanesulfonylamino-benzoylamino)-methyl]-morpholine-4-carboxylicacid benzyl ester 448.3 449.

2-[(3-Fluoro-4-hydroxy-benzoylamino)-methyl]-morpholine-4-carboxylicacidbenzyl ester 389.3 450.

2-[(4-Hydroxy-3-methyl-benzoylamino)-methyl]-morpholine-4-carboxylicacid benzyl ester 385.3 451.

2-[(4-Hydroxy-benzoylamino)-methyl]-morpholine-4-carboxylic acid4-ethyl-benzyl ester 399.4 452.

2-[(4-Hydroxy-benzoylamino)-methyl]-morpholine-4-carboxylic acidthiophen-3-ylmethyl ester 377.2 453.

2-[(4-Hydroxy-benzoylamino)-methyl]-morpholine-4-carboxylic acidthiophen-2-ylmethyl ester 377.2 454.

2-[(4-Hydroxy-benzoylamino)-methyl]-morpholine-4-carboxylic acidpyridin-4-ylmethyl ester 372.2 455.

2-[(4-Hydroxy-benzoylamino)-methyl]-morpholine-4-carboxylic acid4-isopropyl-benzyl ester 413.3 456.

2-[(4-Hydroxy-benzoylamino)-methyl]-morpholine-4-carboxylic acid4-tert-butyl-benzyl ester 427.3 457.

2-[(4-Hydroxy-benzoylamino)-methyl]-morpholine-4-carboxylic acid2-chloro-benzyl ester 405.2 458.

2-[(4-Hydroxy-benzoylamino)-methyl]-morpholine-4-carboxylic acid3-chloro-benzyl ester 405.2 459.

2-[(4-Hydroxy-benzoylamino)-methyl]-morpholine-4-carboxylic acid2-methyl-benzyl ester 385.3 460.

2-[(4-Hydroxy-benzoylamino)-methyl]-morpholine-4-carboxylic acid3-methyl-benzyl ester 385.3 461.

2-[(4-Hydroxy-benzoylamino)-methyl]-morpholine-4-carboxylicacidbenzo[1,3]dioxol-5-ylmethyl ester 415.3 462.

2-[(4-Hydroxy-benzoylamino)-methyl]-morpholine-4-carboxylic acidphenethyl ester 385.3 463.

2-[(4-Hydroxy-benzoylamino)-methyl]-morpholine-4-carboxylic acidbiphenyl-4-ylmethyl ester 447.3 464.

2-[(4-Hydroxy-benzoylamino)-methyl]-morpholine-4-carboxylic acid3-trifluoromethyl-benzyl ester 439.3 465.

2-[(4-Hydroxy-benzoylamino)-methyl]-morpholine-4-carboxylic acid4-trifluoromethyl-benzyl ester 439.3 466.

2-[(4-Hydroxy-benzoylamino)-methyl]-morpholine-4-carboxylic acid3-fluoro-benzyl ester 389.3 467.

2-[(4-Hydroxy-benzoylamino)-methyl]-morpholine-4-carboxylic acid4-trifluoromethoxy-benzyl ester 455.3 468.

2-[(4-Hydroxy-benzoylamino)-methyl]-morpholine-4-carboxylic acid3,4-dimethyl-benzyl ester 399.3 469.

2-[(4-Hydroxy-benzoylamino)-methyl]-morpholine-4-carboxylic acid2,4-dimethyl-benzyl ester 399.3 470.

2-[(4-Hydroxy-benzoylamino)-methyl]-morpholine-4-carboxylic acid1-phenyl-ethyl ester 385.3 471.

2-[(4-Hydroxy-benzoylamino)-methyl]-morpholine-4-carboxylic acid1-phenyl-ethyl ester 385.3 472.

2-[(4-Hydroxy-benzoylamino)-methyl]-morpholine-4-carboxylic acid4-methylsulfanyl-benzyl ester 417.3 473.

2-[(4-Hydroxy-benzoylamino)-methyl]-morpholine-4-carboxylic acid3-trifluoromethoxy-benzyl ester 455.3 474.

2-[(4-Hydroxy-benzoylamino)-methyl]-morpholine-4-carboxylic acid2-trifluoromethoxy-benzyl ester 455.3 475.

2-[(4-Hydroxy-benzoylamino)-methyl]-morpholine-4-carboxylic acid6-chloro-pyridin-3-ylmethyl ester 406.2 476.

2-[(4-Hydroxy-benzoylamino)-methyl]-morpholine-4-carboxylic acid6-methyl-pyridin-3-ylmethyl ester 386.3 477.

2-[(4-Hydroxy-benzoylamino)-methyl]-morpholine-4-carboxylic acid4-cyclopropyl-benzyl ester 411.3 478.

2-[(4-Hydroxy-benzoylamino)-methyl]-morpholine-4-carboxylic acidindan-2-yl ester 397.3 479.

2-[(4-Hydroxy-benzoylamino)-methyl]-morpholine-4-carboxylic acid5-methyl-thiophen-2-ylmethyl ester 391.3 480.

2-[(4-Hydroxy-benzoylamino)-methyl]-morpholine-4-carboxylic acid1-oxy-pyridin-4-ylmethyl ester 388.2 481.

4-Hydroxy-N-[4-(2-phenyl-cyclopropanecarbonyl)-morpholin-2-ylmethyl]-benzamide381.3 482.

2-[(4-Hydroxy-benzoylamino)-methyl]-morpholine-4-carboxylic acid3-fluoro-benzyl ester 389.4 483.

2-[(4-Hydroxy-benzoylamino)-methyl]-morpholine-4-carboxylic acidbiphenyl-4-ylmethyl ester 447.4 484.

2-[(4-Hydroxy-benzoylamino)-methyl]-morpholine-4-carboxylic acid2-fluoro-benzyl ester 389.4 485.

2-[(4-Hydroxy-benzoylamino)-methyl]-morpholine-4-carboxylic acid4-benzyloxy-benzyl ester 477.25 486.

2-[(4-Hydroxy-benzoylamino)-methyl]-morpholine-4-carboxylic acid2,4-dichloro-benzyl ester 439.3 487.

2-[(4-Hydroxy-benzoylamino)-methyl]-morpholine-4-carboxylic acid2,4-difluoro-benzyl ester 407.4 488.

2-[(4-Hydroxy-benzoylamino)-methyl]-morpholine-4-carboxylic acid3,4-difluoro-benzyl ester 407.4 489.

2-[(4-Hydroxy-benzoylamino)-methyl]-morpholine-4-carboxylic acid4-fluoro-3-trifluoromethyl-benzyl ester 457.4 490.

2-[(4-Hydroxy-benzoylamino)-methyl]-morpholine-4-carboxylic acid2-fluoro-4-trifluoromethyl-benzyl ester 457.4 491.

2-[(4-Hydroxy-benzoylamino)-methyl]-morpholine-4-carboxylic acid3,5-dichloro-benzyl ester 439.3 492.

2-[(4-Hydroxy-benzoylamino)-methyl]-morpholine-4-carboxylic acid2,5-dichloro-benzyl ester 439.3 493.

2-[(4-Hydroxy-benzoylamino)-methyl]-morpholine-4-carboxylic acid3-trifluoromethyl-benzyl ester 439.4 494.

2-[(4-Hydroxy-benzoylamino)-methyl]-morpholine-4-carboxylic acid3-methyl-benzyl ester 385.4 495.

2-[(4-Hydroxy-benzoylamino)-methyl]-morpholine-4-carboxylic acid3-chloro-benzyl ester 405.3 496.

2-[(4-Hydroxy-benzoylamino)-methyl]-morpholine-4-carboxylic acid4-methylsulfanyl-benzyl ester 417.3 497.

2-[(4-Hydroxy-benzoylamino)-methyl]-morpholine-4-carboxylic acid2-chloro-benzyl ester 405.3 498.

2-{[(5-Hydroxy-pyridine-2-carbonyl)-amino]-methyl}-morpholine-4-carboxylicacid 4-fluoro-benzyl ester 390.3 499.

2-[(3-Fluoro-4-hydroxy-benzoylamino)-methyl]-morpholine-4-carboxylicacid 4-fluoro-benzyl ester 407.3 500.

2-[(4-Hydroxy-benzoylamino)-methyl]-5-methyl-morpholine-4-carboxylicacidbenzyl ester 385.4 501.

2-[(4-Hydroxy-benzoylamino)-methyl]-5-methyl-morpholine-4-carboxylicacid4-methyl-benzyl ester 399.3 502.

2-[(3-Chloro-4-hydroxy-benzoylamino)-methyl]-morpholine-4-carboxylicacid 4-fluoro-benzyl ester 423.3 503.

2.[(3,5-Dichloro-4-hydroxy-benzoylamino)-methyl]-morpholine-4-carboxylicacid 4-fluoro-benzyl ester 457.2 504.

2-{[(6-Hydroxy-pyridazine-3-carbonyl)-amino]-methyl}-morpholine-4-carboxylicacid 4-fluoro-benzyl ester 391.4 505.

2-[(4-Hydroxy-benzoylamino)-methyl]-5-methyl-morpholine-4-carboxylicacid4-fluoro-benzyl ester 403.4 506.

2-[(4-Hydroxy-benzoylamino)-methyl]-5-methyl-morpholine-4-carboxylicacidbenzyl ester 385.3 507.

2-[(4-Hydroxy-benzoylamino)-methyl]-5-methyl-morpholine-4-carboxylicacid4-methyl-benzyl ester 399.4 508.

2-(4-Hydroxy-benzoylamino)-methyl]-5-methyl-morpholine-4-carboxylicacid4-fluoro-benzyl ester 403.3 509.

2-[2,3-Difluoro-4-hydroxy-benzoylamino)-methyl]-morpholine-4-carboxylicacid 4-fluoro-benzyl ester 425.2 510.

2-[(3-Bromo-4-hydroxy-benzoylamino)-methyl]-morpholine-4-carboxylic acid4-fluoro-benzyl ester 467.2 511.

2-[(2-Chloro-4-hydroxy-benzoylamino)-methyl]-morpholine-4-carboxylicacid 4-fluoro-benzyl ester 423.2 512.

2-[(4-Hydroxy-benzoylamino)-methyl]-morpholine-4-carboxylic acidpyridin-4-ylmethyl ester 372.3 513.

2-[(4-Hydroxy-benzoylamino)-methyl]-morpholine-4-carboxylic acidpyridin-3-ylmethyl ester 372.3 514.

2-[(4-Hydroxy-benzoylamino)-methyl]-morpholine-4-carboxylic acidpyridin-2-ylmethyl ester 372.3 515.

2-[(4-Hydroxy-benzoylamino)-methyl]-morpholine-4-carboxylic acid benzylester 371.3 516.

2-[(4-Hydroxy-benzoylamino)-methyl]-morpholine-4-carboxylic acid4-fluoro-benzyl ester 389.3 517.

2-[(4-Hydroxy-benzoylamino)-methyl]-morpholine-4-carboxylic acid4-chloro-benzyl ester 405.3 518.

2-[(4-Hydroxy-benzoylamino)-methyl]-morpholine-4-carboxylic acid4-methanesulfinyl-benzyl ester 433.3 519.

2-[(4-Cyano-benzoylamino)-methyl]-morpholine-4-carboxylic acid4-fluoro-benzyl ester 398.4 520.

2-[(4-Hydroxymethyl-benzoylamino)-methyl]-morpholine-4-carboxylicacid4-fluoro-benzyl ester 403.4 521.

2-{[(2-Oxo-2,3-dihydro-1H-indole-5-carbonyl)-amino]-methyl}-morpholine-4-carboxylicacid benzyl ester 410.3 522.

2-{[(2-Oxo-1,2,3,4-tetrahydro-quinoline-6-carbonyl)-amino]-methyl}-morpholine-4-carboxylicacid benzyl ester 424.4 523.

4-Methylbenzyl4-({[(2,5-dimethyl-1H-pyrrol-3-yl)carbonyl]amino}methyl)piperidine1-carboxylate370.2 524.

4-Methylbenzyl4-{[(2-chloroisonicotinoyl)amino]methyl}piperidine-1-carboxylate 402.1525.

Benzyl4-({[(5-hydroxypyridin-2-yl)carbonyl]amino}methyl)piperidine-1-carboxylate370.3 526.

Benzyl4-({[4-hydroxy-3-(trifluoromethyl)benzoyl]amino}methyl)piperidine-1-carboxylate437.4 527.

Benzyl 4-{[(2-fluoroisonicotinoyl)amino]methyl}piperidine-1-carboxylate372.4 528.

Benzyl4-{[(2,3-difluoro-4-hydroxybenzoyl)amino]methyl}piperidine-1-carboxylate405.3 529.

Benzyl 4-{[(pyridazin-4-ylcarbonyl)amino]methyl}piperidine-1-carboxylate355.3 530.

Benzyl4-{[(4-hydroxy-3-methoxybenzoyl)amino]methyl}piperidine-1-carboxylate399.4 531.

Benzyl4-{[(2,6-dichloroisonicotinoyl)amino]methyl}piperidine-1-carboxylate423.3 532.

4-Methylbenzyl4-({[4-(hydroxymethyl)benzoyl]amino}methyl)piperidine-1-carboxylate397.4 533.

4-Methylbenzyl4-({[4-(methoxycarbonyl)benzoyl]amino}methyl)piperidine-1-carboxylate425.5 534.

4-Methylbenzyl4-({[4-(1-hydroxyethyl)benzoyl]amino}methyl)piperidine-1-carboxylate411.4 535.

4-Methylbenzyl4-({[3-(methoxycarbonyl)benzoyl]amino}methyl)piperidine-1-carboxylate425.4 536.

4-Methylbenzyl4-({[4-(2-hydroxyethyl)benzoyl]amino}methyl)piperidine-1-carboxylate411.3 537.

4-Methylbenzyl4-({[4-(1H-imidazol-2-yl)benzoyl]amino}methyl)piperidine-1-carboxylate433.3 538.

4-Methylbenzyl4-({[4-(trifluoroacetyl)benzoyl]amino}methyl)piperidine-1-carboxylate481.2 539.

4-Methylbenzyl4-{[(4-{[(tert-butoxycarbonyl)amino]methyl}benzoyl)amino]methyl}piperidine-1-carboxylate496.4 540.

4-Methylbenzyl4-[({[2-(hydroxymethyl)-1,3-thiazol-4-yl]carbonyl}amino)methyl]piperidine-1-carboxylate404.2 541.

7-[(4-Hydroxy-benzoylamino)-methyl]-[1,4]oxazepane-4-carboxylic acid4-methyl-benzyl ester 399.4 542.

7-[(4-Hydroxy-benzoylamino)-methyl]-[1,4]oxazepane-4-carboxylic acid4-fluoro-benzyl ester 403.4 543.

7-{[(1H-Pyrrole-3-carbonyl)-amino]-methyl}-[1,4]oxazepane-4-carboxylicacidbenzyl ester 358.3 544.

7-[(4-Hydroxy-benzoylamino)-methyl]-[1,4]oxazepane-4-carboxylic acid4-chloro-benzyl ester 419.4 545.

4-[(4-Hydroxy-benzoylamino)-methyl]-azepane-1-carboxylic acid benzylester 383.4 546.

4-[(4-Hydroxy-benzoylamino)-methyl]-azepane-1-carboxylic acid benzylester 383.4 547.

4-[(4-Hydroxy-benzoylamino)-methyl]-azepane-1-carboxylic acid benzylester 383.4 548.

7-[(4-Hydroxy-benzoylamino)-methyl]-[1,4]oxazepane-4-carboxylicacidbenzyl ester 385.4 549.

7-[(4-Hydroxy-benzoylamino)-methyl]-[1,4]oxazepane-4-carboxylicacidbenzyl ester 385.4

1. A compound having the Formula (I):

or a pharmaceutically acceptable salt thereof, wherein NonAr is anonaromatic 6 membered ring containing 1 nitrogen ring atom, wherein theremaining ring atoms are carbon; A is a phenyl optionally substitutedwith 1–5 substituents, each substituent independently is C₁₋₄alkyl,C₃₋₇cycloalkyl, —CF₃, halogen, —OH, —CN, imidazolyl,—C₀₋₄alkyl-N(C₀₋₅alkyl)(C₀₋₅alkyl), —O—C₁₋₄alkyl, —C(O)—C₀₋₄alkyl,—C(O)—O—C₀₋₄alkyl, —O—C(O)—C₀₋₄alkyl, —O—C(O)—C₀₋₄alkylphenyl,—C₀₋₄alkyl—N(C₀₋₅alkyl)-C(O)—C₀₋₄alkyl,—C₀₋₄alkyl-N(C₀₋₅alkyl)-C(O)—O—C₀₋₄alkyl,—C₀₋₄alkyl-N(C₀₋₅alkyl)-C(O)—O—C₁₋₄alkyl, or —NHSO₂—C₁₋₄alkyl,—O—C₁₋₄alkylphenyl, or hydroxyiminoethyl; any alkyl optionallysubstituted with 1–6 —OH or halogen; or A is pyrrolyl, imidazolyl,pyrazolyl, triazolyl, thiophenyl, thiazolyl, thiadiazolyl, oxazolyl, orisoxazolyl, each optionally substituted with 1–3 substituents, eachsubstituent independently is —C₁₋₄alkyl, —C₃₋₇cycloalkyl, —CF₃, halogen,—OH, —CN, —C₁₋₄alkoxyl, phenyl, —C₀₋₄alkyl-N(C₀₋₅alkyl)(C₀₋₅alkyl),—C₁₋₄ hydroxyalkyl; or A is pyridyl, pyradazinyl, pyrimidinyl, orpyrazinyl, each optionally substituted with 1–5 substituents; eachsubstituent independently is —C₁₋₄alkyl, —C₃₋₇cycloalkyl, —CF₃, halogen,—OH, —CN, phenyl, pyrrolidinyl, azepanyl, —C₁₋₄hydroxyalkyl,—C₁₋₄alkoxy, (CH₃)₂N—(CH₂)₂—NH—, —SO₂—C₁₋₄alkyl,—C₀₋₄alkyl-N(C₀₋₅alkyl)(C₀₋₅alkyl),—C₀₋₄alkyl-N(C₃₋₆cycloalkyl)(C₀₋₅alkyl),—C₀₋₄alkyl-N(C₀₋₅alkyl)(C₁₋₄alkyloxyC₁₋₄alkyl),—N(C₀₋₅alkyl)-C₀₋₄alkyl-phenyl(C₁₋₄alkoxyl)₀₋₃,—N(C₀₋₅alkyl)—C₀₋₄alkylthiaphenyl, dimethoxyphenyl-CH₂—NH—; any phenyloptionally substituted with 1–5 —OH, halogen, or C₁₋₄alkyl; any alkyloptionally substituted with 1–5 —OH or halogen; or the substituent takenwith a neighboring bond is ═O; or A is pyrrolophenyl, pyrazolophenyl,triazolophenyl, pyridinoimidazolyl, naphthyridinyl,tetrahydrocyclopentopyrazolyl, quinolinyl, pyrimidinopyrazololyl,benzothiazolyl, benzoimidazolyl, benzoxazolonyl, oxodihydrobenzoxazolyl,indolinonyl, oxadihydroquinolinyl, oxatetrahydroquinolinyl, or purinyl,each optionally substituted with 1–5 substituents, each substituentindependently is —C₁₋₄alkyl, —C₃₋₇cycloalkyl, —CF₃, halogen, —OH, or—CN; B is aryl(CH₂)₀₋₃—O—(CH₂)₀₋₂—C(O)—,heteroaryl(CH₂)₁₋₃—O—(CH₂)₀₋₂—C(O)—, indanyl(CH₂)₀₋₃—O—(CH₂)₀₋₂—C(O)—,aryl-cyclopropyl-C(O)—(CH₂)₀₋₂—, heteroaryl(CH₂)₁₋₃—C(O)—,aryl(CH₂)₁₋₃—, heteroaryl(CH₂)₁₋₃—, aryl(CH₂)₁₋₃—NH—C(O)—,aryl(CH₂)₁₋₃—NH—C(NCN)—, aryl(CH₂)₁₋₃—SO₂—,aryl(CH₂)₀₋₃—S—(CH₂)₀₋₂—C(O)—, or heteroaryl(CH₂)₁₋₃—SO₂— wherein any ofthe aryl or heteroaryl is optionally substituted by 1–5 substituents,each substituent independently is C₁₋₄alkyl, C₃₋₆cycloalkyl, C₁₋₄alkoxy,trifluoromethyl, phenyl, —O—C₁₋₄alkylphenyl, —S(O)—C₁₋₄alkyl, bromo,fluoro, chloro, or 2 substituents together form methylene dioxy; any(CH₂) optionally is substituted with C₁₋₂alkyl; or B is

wherein the phenyl is optionally substituted by 1–3 substituents, eachsubstituent independently is C₁₋₄alkyl, C₃₋₆cycloalkyl, C₁₋₄alkoxy,trifluoromethyl, bromo, fluoro, or chloro; and X is H, OH, F, C₁₋₄alkyl,C₁₋₄alkoxy, —N(C₀₋₅alkyl)(C₀₋₅alkyl), phenyl, or ═O.
 2. The compoundaccording to claim 1, or a pharmaceutically acceptable salt thereof,wherein A is a phenyl optionally substituted with 1–5 substituents, eachsubstituent independently is C₁₋₄alkyl, C₃₋₇cycloalkyl, —CF₃, halogen,—OH, —CN, imidazolyl, —C₀₋₄alkyl-N(C₀₋₅alkyl)(C₀₋₅alkyl), —O—C₁₋₄alkyl,—C(O)—C₀₋₄alkyl, —C(O)—O—C₀₋₄alkyl, —O—C(O)—C₀₋₄alkyl,—O—C(O)—C₀₋₄alkylphenyl, —C₀₋₄alkyl-N(C₀₋₅alkyl)-C(O)—C₀₋₄alkyl,—C₀₋₄alkyl-N(C₀₋₅alkyl)-C(O)—O—C₀₋₄alkyl,—C₀₋₄alkyl-N(C₀₋₅alkyl)-C(O)—O—C₁₋₄alkyl, or —NHSO₂—C₁₋₄alkyl,—O—C₁₋₄alkylphenyl, or hydroxyiminoethyl; any alkyl optionallysubstituted with 1–6 —OH or halogen.
 3. The compound according to claim1, or a pharmaceutically acceptable salt thereof, wherein A is pyrrolyl,imidazolyl, pyrazolyl, triazolyl, thiophenyl, thiazolyl, thiadiazolyl,oxazolyl, or isoxazolyl, each optionally substituted with 1–3substituents, each substituent independently is —C₁₋₄alkyl,—C₃₋₇cycloalkyl, —CF₃, halogen, —OH, —CN, phenyl, —C₁₋₄hydroxyalkyl. 4.The compound according to claim 1, or a pharmaceutically acceptable saltthereof, wherein A is pyridyl, pyradazinyl, pyrimidinyl, or pyrazinyl,each optionally substituted with 1–3 substituents, each substituentindependently is —C₁₋₄alkyl, —C₃₋₇cycloalkyl, —CF₃, halogen, —OH, —CN,phenyl, —C₁₋₄hydroxyalkyl, —C₁₋₄alkoxy, (CH₃)₂N—(CH₂)₂—NH—,—C₀₋₄alkyl-N(C₀₋₄alkyl)(C₀₋₄alkyl), dimethoxyphenyl-CH₂—NH—, or thesubstituent taken with a neighboring bond is ═O.
 5. The compoundaccording to claim 1, or a pharmaceutically acceptable salt thereof,wherein A is pyrrolophenyl, pyrazolophenyl, triazolophenyl,pyridinoimidazolyl, naphthyridinyl, tetrahydrocyclopentopyrazolyl,quinolinyl, pyrimidinopyrazololyl, benzothiazolyl, benzoimidazolyl, orpurinyl, each optionally substituted with 1–3 substituents, eachsubstituent independently is —C₁₋₄alkyl, —C₃₋₇cycloalkyl, —CF₃, halogen,—OH, or —CN.
 6. The compound according to claim 1, wherein said compoundis

or a pharmaceutically acceptable salt thereof.
 7. The compound accordingto claim 1, wherein said compound is

or a pharmaceutically acceptable salt thereof.
 8. The compound accordingto claim 1, wherein said compound is

or a pharmaceutically acceptable salt thereof.
 9. The compound accordingto claim 1, wherein said compound is

or a pharmaceutically acceptable salt thereof.
 10. The compoundaccording to claim 1, wherein said compound is

or a pharmaceutically acceptable salt thereof.
 11. The compoundaccording to claim 1, wherein said compound is

or a pharmaceutically acceptable salt thereof.
 12. A pharmaceuticalcomposition comprising an inert carrier and an effective amount of acompound according to claim
 1. 13. The pharmaceutical compositionaccording to claim 12 for the treatment of pain.
 14. The pharmaceuticalcomposition according to claim 12 for the treatment of migraine,depression, anxiety, schizophrenia, Parkinson's disease, or stroke. 15.A method of treating pain comprising a step of administering to one inneed of such treatment a therapeutically effective amount of a compoundaccording to claim
 1. 16. A method of treating migraine, depression,anxiety, schizophrenia, Parkinson's disease, or stroke comprising a stepof administering to one in need of such treatment a therapeuticallyeffective amount of a compound according to claim 1.